3EHU

Crystal structure of the extracellular domain of human corticotropin releasing factor receptor type 1 (CRFR1) in complex with CRF

External Resource: Annotation

Domain Annotation: SCOP2 Classification
Domain Annotation: ECOD Classification
Domain Annotation: CATH
Protein Family Annotation
Gene Ontology: Gene Product Annotation
InterPro: Protein Family Classification
Pharos: Disease Associations
Protein Modification Annotation

Domain Annotation: SCOP2 Classification SCOP2 Database Homepage

Chains	Type	Family Name	Domain Identifier	Family Identifier	Provenance Source (Version)
A	SCOP2B Superfamily	FnI-like domain	8086307	3000979	SCOP2B (2022-06-29)
A	SCOP2B Superfamily	Type 2 solute binding protein-like	8058187	3000083	SCOP2B (2022-06-29)
B	SCOP2B Superfamily	FnI-like domain	8086307	3000979	SCOP2B (2022-06-29)
B	SCOP2B Superfamily	Type 2 solute binding protein-like	8058187	3000083	SCOP2B (2022-06-29)

Domain Annotation: ECOD Classification ECOD Database Homepage

Chains	Family Name	Domain Identifier	Architecture	Possible Homology	Homology	Topology	Family	Provenance Source (Version)
A	HRM_1	e3ehuA2	A: few secondary structure elements	X: Hormone receptor domain (HRM, Pfam 02793) (From Topology)	H: Hormone receptor domain (HRM, Pfam 02793) (From Topology)	T: Hormone receptor domain (HRM, Pfam 02793)	F: HRM_1	ECOD (1.6)
B	HRM_1	e3ehuB2	A: few secondary structure elements	X: Hormone receptor domain (HRM, Pfam 02793) (From Topology)	H: Hormone receptor domain (HRM, Pfam 02793) (From Topology)	T: Hormone receptor domain (HRM, Pfam 02793)	F: HRM_1	ECOD (1.6)

Domain Annotation: CATH CATH Database Homepage

Chain	Domain	Class	Architecture	Topology	Homology	Provenance Source (Version)
A	3.40.190.10	Alpha Beta	3-Layer(aba) Sandwich	D-Maltodextrin-Binding Protein	domain 2	CATH (4.3.0)
A	4.10.1240.10	Few Secondary Structures	Irregular	Hormone receptor fold	GPCR, family 2, extracellular hormone receptor domain	CATH (4.3.0)
B	3.40.190.10	Alpha Beta	3-Layer(aba) Sandwich	D-Maltodextrin-Binding Protein	domain 2	CATH (4.3.0)
B	4.10.1240.10	Few Secondary Structures	Irregular	Hormone receptor fold	GPCR, family 2, extracellular hormone receptor domain	CATH (4.3.0)

Protein Family Annotation Pfam Database Homepage

Chains	Accession	Name	Description	Comments	Source
C, D	PF00473	Corticotropin-releasing factor family (CRF)	Corticotropin-releasing factor family	-	Family
A, B	PF02793	Hormone receptor domain (HRM)	Hormone receptor domain	-	Family

Gene Ontology: Gene Product Annotation Gene Ontology Database Homepage

Chains	Polymer	Molecular Function	Biological Process	Cellular Component
C, D	Corticoliberin	corticotropin-releasing hormone receptor 2 binding peptide hormone receptor binding protein binding binding corticotropin-releasing hormone receptor binding signaling receptor binding G protein-coupled receptor binding hormone receptor binding neuropeptide receptor binding corticotropin-releasing hormone activity hormone activity molecular function activator activity molecular function regulator activity signaling receptor regulator activity corticotropin-releasing hormone receptor 2 binding peptide hormone receptor binding protein binding binding corticotropin-releasing hormone receptor binding signaling receptor binding G protein-coupled receptor binding hormone receptor binding neuropeptide receptor binding corticotropin-releasing hormone activity hormone activity molecular function activator activity molecular function regulator activity signaling receptor regulator activity receptor ligand activity signaling receptor activator activity neuropeptide activity neuropeptide hormone activity corticotropin-releasing hormone receptor 1 binding	response to stimulus response to chemical response to xenobiotic stimulus steroid metabolic process lipid biosynthetic process primary metabolic process glucocorticoid metabolic process glucocorticoid biosynthetic process organic cyclic compound metabolic process organic substance metabolic process biosynthetic process organic cyclic compound biosynthetic process organic substance biosynthetic process metabolic process response to stimulus response to chemical response to xenobiotic stimulus steroid metabolic process lipid biosynthetic process primary metabolic process glucocorticoid metabolic process glucocorticoid biosynthetic process organic cyclic compound metabolic process organic substance metabolic process biosynthetic process organic cyclic compound biosynthetic process organic substance biosynthetic process metabolic process steroid biosynthetic process steroid hormone biosynthetic process lipid metabolic process regulation of cellular process cellular biosynthetic process positive regulation of biological process positive regulation of cellular metabolic process positive regulation of macromolecule biosynthetic process positive regulation of metabolic process positive regulation of biosynthetic process positive regulation of macromolecule metabolic process positive regulation of cellular process regulation of biosynthetic process regulation of biological process cellular metabolic process biological regulation regulation of cellular metabolic process regulation of macromolecule metabolic process gene expression macromolecule biosynthetic process regulation of cellular biosynthetic process regulation of gene expression positive regulation of gene expression regulation of macromolecule biosynthetic process cellular process macromolecule metabolic process regulation of metabolic process positive regulation of cellular biosynthetic process cellular response to stimulus positive regulation of cell communication positive regulation of signal transduction signaling regulation of signal transduction intracellular signal transduction cell communication positive regulation of response to stimulus cAMP-mediated signaling regulation of intracellular signal transduction intracellular signaling cassette signal transduction regulation of signaling positive regulation of intracellular signal transduction positive regulation of cAMP-mediated signaling regulation of response to stimulus regulation of cell communication regulation of cAMP-mediated signaling positive regulation of signaling multi-multicellular organism process multicellular organismal process reproductive process parturition multi-organism reproductive process regulation of circadian sleep/wake cycle negative regulation of biological process negative regulation of circadian sleep/wake cycle, REM sleep regulation of circadian rhythm regulation of behavior sleep regulation of multicellular organismal process circadian sleep/wake cycle, sleep rhythmic process negative regulation of behavior circadian sleep/wake cycle rhythmic behavior circadian rhythm regulation of circadian sleep/wake cycle, REM sleep negative regulation of circadian sleep/wake cycle, sleep negative regulation of circadian rhythm behavior circadian behavior circadian sleep/wake cycle, REM sleep regulation of circadian sleep/wake cycle, sleep negative regulation of multicellular organismal process circadian sleep/wake cycle process response to organic substance response to ketone response to lipid cellular response to endogenous stimulus response to hormone response to steroid hormone cellular response to organic substance cellular response to ketone cellular response to steroid hormone stimulus response to organic cyclic compound cellular response to hormone stimulus response to endogenous stimulus cellular response to dexamethasone stimulus response to glucocorticoid cellular response to organic cyclic compound cellular response to glucocorticoid stimulus response to oxygen-containing compound cellular response to oxygen-containing compound cellular response to corticosteroid stimulus response to corticosteroid cellular response to chemical stimulus cellular response to lipid response to dexamethasone response to alcohol response to corticosterone response to mineralocorticoid trans-synaptic signaling cell-cell signaling chemical synaptic transmission synaptic signaling anterograde trans-synaptic signaling synaptic transmission, dopaminergic regulation of localization system process nitrogen compound transport regulation of system process localization regulation of biological quality regulation of peptide hormone secretion positive regulation of corticotropin secretion regulation of hormone levels positive regulation of peptide hormone secretion organic substance transport establishment of localization regulation of secretion endocrine hormone secretion positive regulation of multicellular organismal process regulation of endocrine process regulation of hormone secretion regulation of peptide secretion transport positive regulation of secretion by cell hormone secretion regulation of corticotropin secretion peptide secretion secretion by cell regulation of secretion by cell positive regulation of hormone secretion positive regulation of secretion amide transport signal release positive regulation of peptide secretion secretion regulation of transport corticotropin secretion regulation of peptide transport export from cell peptide transport endocrine process positive regulation of transport peptide hormone secretion hormone transport regulation of calcium ion import regulation of calcium ion transport positive regulation of calcium ion transport positive regulation of calcium ion import regulation of monoatomic ion transport calcium ion transport metal ion transport positive regulation of monoatomic ion transport monoatomic ion transport calcium ion import monoatomic cation transport regulation of metal ion transport response to aldosterone hormone-mediated signaling pathway cell death apoptotic signaling pathway hormone-mediated apoptotic signaling pathway apoptotic process programmed cell death corticosterone secretion positive regulation of steroid hormone secretion regulation of glucocorticoid secretion positive regulation of glucocorticoid secretion regulation of steroid hormone secretion positive regulation of corticosteroid hormone secretion lipid transport regulation of corticosteroid hormone secretion positive regulation of lipid transport lipid export from cell glucocorticoid secretion corticosteroid hormone secretion regulation of corticosterone secretion steroid hormone secretion regulation of lipid transport organic hydroxy compound transport positive regulation of corticosterone secretion lipid localization positive regulation of lipid localization regulation of lipid localization macromolecule localization response to ether positive regulation of cortisol secretion cortisol secretion regulation of cortisol secretion chemical homeostasis homeostatic process monoatomic ion homeostasis response to stress multicellular organismal response to stress response to pain response to estrogen female pregnancy regulation of signaling receptor activity regulation of transmembrane transporter activity regulation of transporter activity regulation of NMDA receptor activity regulation of monoatomic ion transmembrane transporter activity transmembrane transport regulation of molecular function regulation of transmembrane transport regulation of neurotransmitter receptor activity negative regulation of luteinizing hormone secretion negative regulation of transport regulation of luteinizing hormone secretion negative regulation of secretion luteinizing hormone secretion negative regulation of hormone secretion negative regulation of secretion by cell negative regulation of gonadotropin secretion gonadotropin secretion negative regulation of signaling negative regulation of cell communication negative regulation of cellular process regulation of gonadotropin secretion regulation of defense response regulation of fear response regulation of behavioral fear response behavioral defense response regulation of response to stress behavioral fear response defense response positive regulation of behavioral fear response fear response positive regulation of fear response positive regulation of behavior positive regulation of defense response developmental process multicellular organism development tube development anatomical structure development animal organ development respiratory tube development lung development respiratory system development system development digestive system process regulation of digestive system process digestion positive regulation of digestive system process head development hypothalamus development forebrain development brain development diencephalon development nervous system development central nervous system development limbic system development diterpenoid metabolic process cellular lipid metabolic process terpenoid metabolic process isoprenoid metabolic process locomotory behavior exploration behavior locomotory exploration behavior response to ethanol cell population proliferation positive regulation of cell population proliferation regulation of cell population proliferation protein localization establishment of protein localization positive regulation of establishment of protein localization carbohydrate homeostasis cellular macromolecule localization establishment of localization in cell positive regulation of insulin secretion involved in cellular response to glucose stimulus positive regulation of insulin secretion establishment of protein localization to extracellular region intracellular glucose homeostasis protein secretion regulation of protein secretion cellular response to carbohydrate stimulus response to glucose glucose homeostasis positive regulation of protein localization insulin secretion involved in cellular response to glucose stimulus cellular localization regulation of protein localization protein localization to extracellular region positive regulation of protein transport response to monosaccharide response to carbohydrate cellular response to hexose stimulus intracellular chemical homeostasis cellular response to monosaccharide stimulus regulation of establishment of protein localization cellular response to glucose stimulus regulation of protein transport positive regulation of protein secretion response to hexose cellular homeostasis protein transport regulation of cellular localization regulation of insulin secretion regulation of insulin secretion involved in cellular response to glucose stimulus insulin secretion adrenal gland development endocrine system development gland development neuron apoptotic process response to immobilization stress monoamine transport serotonin secretion regulation of serotonin secretion serotonin transport cellular response to nitrogen compound response to organonitrogen compound response to nitrogen compound response to alkaloid cellular response to organonitrogen compound cellular response to cocaine cellular response to alkaloid response to cocaine negative regulation of amine transport regulation of catecholamine secretion epinephrine secretion catecholamine transport epinephrine transport regulation of epinephrine secretion negative regulation of catecholamine secretion organic cation transport catecholamine secretion amine transport negative regulation of epinephrine secretion regulation of amine transport learning or memory nervous system process cognition learning associative learning regulation of systemic arterial blood pressure circulatory system process regulation of blood pressure negative regulation of systemic arterial blood pressure blood circulation negative regulation of blood pressure positive regulation of phosphorylation regulation of protein modification process regulation of protein phosphorylation positive regulation of protein metabolic process positive regulation of phosphate metabolic process regulation of primary metabolic process positive regulation of protein modification process regulation of phosphate metabolic process phosphate-containing compound metabolic process protein metabolic process positive regulation of protein phosphorylation phosphorus metabolic process protein modification process organonitrogen compound metabolic process protein phosphorylation positive regulation of phosphorus metabolic process phosphorylation regulation of protein metabolic process macromolecule modification regulation of phosphorus metabolic process regulation of phosphorylation inflammatory response regulation of circadian sleep/wake cycle, wakefulness positive regulation of circadian rhythm circadian sleep/wake cycle, wakefulness positive regulation of circadian sleep/wake cycle, wakefulness negative regulation of cellular metabolic process negative regulation of macromolecule metabolic process negative regulation of metabolic process negative regulation of cellular biosynthetic process negative regulation of gene expression negative regulation of biosynthetic process negative regulation of macromolecule biosynthetic process modulation of chemical synaptic transmission long-term synaptic potentiation regulation of synaptic plasticity positive regulation of synaptic transmission regulation of trans-synaptic signaling negative regulation of norepinephrine secretion norepinephrine transport norepinephrine secretion regulation of norepinephrine secretion regulation of glucagon secretion negative regulation of peptide hormone secretion glucagon secretion negative regulation of peptide secretion negative regulation of glucagon secretion	somatodendritic compartment cell body perikaryon neuronal cell body cellular anatomical entity extracellular region extracellular space axon cell projection main axon neuron projection varicosity plasma membrane bounded cell projection synapse somatodendritic compartment cell body perikaryon neuronal cell body cellular anatomical entity extracellular region extracellular space axon cell projection main axon neuron projection varicosity plasma membrane bounded cell projection synapse cell junction
A, B	FUSION PROTEIN OF CRFR1 EXTRACELLULAR DOMAIN AND MBP	transporter activity carbohydrate transmembrane transporter activity transmembrane transporter activity oligosaccharide binding binding disaccharide binding carbohydrate binding maltose binding corticotrophin-releasing factor receptor activity molecular transducer activity G protein-coupled receptor activity transmembrane signaling receptor activity signaling receptor activity amide binding transporter activity carbohydrate transmembrane transporter activity transmembrane transporter activity oligosaccharide binding binding disaccharide binding carbohydrate binding maltose binding corticotrophin-releasing factor receptor activity molecular transducer activity G protein-coupled receptor activity transmembrane signaling receptor activity signaling receptor activity amide binding peptide hormone binding hormone binding corticotropin-releasing hormone binding peptide receptor activity G protein-coupled peptide receptor activity	cellular response to stimulus cellular response to stress response to stimulus DNA damage response response to stress cellular process cell chemotaxis chemotaxis response to external stimulus cellular response to chemical stimulus taxis response to chemical cell migration cell motility cellular response to stimulus cellular response to stress response to stimulus DNA damage response response to stress cellular process cell chemotaxis chemotaxis response to external stimulus cellular response to chemical stimulus taxis response to chemical cell migration cell motility locomotion localization transport organic substance transport carbohydrate transport oligosaccharide transport disaccharide transport establishment of localization maltose transport polysaccharide localization dextrin transport macromolecule localization maltodextrin transmembrane transport polysaccharide transport response to organic substance response to disaccharide response to oxygen-containing compound detection of maltose stimulus detection of stimulus response to carbohydrate detection of chemical stimulus detection of disaccharide stimulus response to maltose detection of carbohydrate stimulus cellular response to nitrogen compound response to corticotropin-releasing hormone response to endogenous stimulus response to organonitrogen compound response to peptide hormone cellular response to peptide hormone stimulus response to nitrogen compound cellular response to oxygen-containing compound cellular response to endogenous stimulus cellular response to organonitrogen compound response to hormone cellular response to organic substance cellular response to corticotropin-releasing hormone stimulus cellular response to hormone stimulus multicellular organismal process system process nitrogen compound transport signaling hormone secretion cell communication peptide secretion secretion by cell amide transport signal release regulation of biological quality regulation of biological process secretion corticotropin secretion regulation of hormone levels biological regulation cell-cell signaling export from cell peptide transport endocrine hormone secretion endocrine process peptide hormone secretion hormone transport behavior exploration behavior multi-multicellular organism process reproductive process female pregnancy multi-organism reproductive process immune response immune system process regulation of localization corticosterone secretion regulation of cellular process regulation of system process regulation of glucocorticoid secretion regulation of steroid hormone secretion lipid transport regulation of corticosteroid hormone secretion regulation of secretion lipid export from cell glucocorticoid secretion regulation of endocrine process corticosteroid hormone secretion regulation of corticosterone secretion regulation of hormone secretion steroid hormone secretion regulation of lipid transport organic hydroxy compound transport regulation of secretion by cell regulation of multicellular organismal process regulation of signaling regulation of transport lipid localization regulation of lipid localization regulation of cell communication general adaptation syndrome general adaptation syndrome, behavioral process multicellular organismal response to stress parturition fear response adult behavior response to alcohol behavioral response to ethanol response to ethanol adenylate cyclase-activating G protein-coupled receptor signaling pathway adenylate cyclase-modulating G protein-coupled receptor signaling pathway G protein-coupled receptor signaling pathway signal transduction cell surface receptor signaling pathway regulation of catalytic activity regulation of lyase activity regulation of molecular function regulation of adenylate cyclase activity regulation of adenylate cyclase activity involved in G protein-coupled receptor signaling pathway regulation of cyclase activity developmental process multicellular organism development adrenal gland development endocrine system development anatomical structure development gland development animal organ development system development positive regulation of adenylate cyclase activity positive regulation of cyclase activity positive regulation of catalytic activity positive regulation of molecular function activation of adenylate cyclase activity positive regulation of lyase activity regulation of calcium ion transmembrane transporter activity regulation of calcium ion transport negative regulation of voltage-gated calcium channel activity negative regulation of ion transmembrane transporter activity negative regulation of calcium ion transmembrane transporter activity negative regulation of biological process negative regulation of transport regulation of voltage-gated calcium channel activity calcium ion transport negative regulation of cation transmembrane transport monoatomic cation transport regulation of monoatomic ion transport inorganic ion transmembrane transport regulation of cation channel activity inorganic cation transmembrane transport transmembrane transport regulation of transmembrane transport negative regulation of calcium ion transmembrane transport negative regulation of cation channel activity monoatomic ion transmembrane transport negative regulation of monoatomic ion transport regulation of transmembrane transporter activity regulation of monoatomic ion transmembrane transport metal ion transport negative regulation of transmembrane transport regulation of transporter activity regulation of calcium ion transmembrane transport monoatomic cation transmembrane transport negative regulation of monoatomic ion transmembrane transport negative regulation of cellular process monoatomic ion transport regulation of metal ion transport regulation of monoatomic ion transmembrane transporter activity negative regulation of transporter activity negative regulation of molecular function negative regulation of calcium ion transport regulation of monoatomic cation transmembrane transport calcium ion transmembrane transport	ATPase dependent transmembrane transport complex protein-containing complex plasma membrane protein complex membrane plasma membrane membrane protein complex cellular anatomical entity transporter complex ATP-binding cassette (ABC) transporter complex cell periphery transmembrane transporter complex ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing maltose transport complex periplasmic space ATPase dependent transmembrane transport complex protein-containing complex plasma membrane protein complex membrane plasma membrane membrane protein complex cellular anatomical entity transporter complex ATP-binding cassette (ABC) transporter complex cell periphery transmembrane transporter complex ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing maltose transport complex periplasmic space outer membrane-bounded periplasmic space cell envelope cell projection neuron projection plasma membrane bounded cell projection membrane-bounded organelle intracellular anatomical structure endosome intracellular vesicle intracellular membrane-bounded organelle endomembrane system intracellular organelle cytoplasmic vesicle organelle cytoplasm vesicle

InterPro: Protein Family Classification InterPro Database Homepage

Chains	Accession	Name	Type
C, D	IPR003620	Urocortin/corticotropin-releasing factor	Family
C, D	IPR018446	Corticotropin-releasing factor conserved site	Conserved Site
C, D	IPR000187	Corticotropin-releasing factor	Domain
A, B	IPR006061	Solute-binding family 1, conserved site	Conserved Site
A, B	IPR006060	Maltose/Cyclodextrin ABC transporter, substrate-binding protein	Family
A, B	IPR006059	Bacterial-type extracellular solute-binding protein	Family
A, B	IPR017983	GPCR, family 2, secretin-like, conserved site	Conserved Site
A, B	IPR003052	GPCR, family 2, corticotropin releasing factor receptor, type 1	Family
A, B	IPR036445	GPCR family 2, extracellular hormone receptor domain superfamily	Homologous Superfamily
A, B	IPR000832	GPCR, family 2, secretin-like	Family
A, B	IPR003051	GPCR, family 2, corticotropin releasing factor receptor	Family
A, B	IPR017981	GPCR, family 2-like, 7TM	Domain
A, B	IPR001879	GPCR, family 2, extracellular hormone receptor domain	Domain

Pharos: Disease Associations Pharos Homepage Annotation

Chains	Drug Target	Associated Disease
C, D	Pharos: P06850	pituitary apoplexy status epilepticus Alzheimer disease Pain stereotypic movement disorder visual epilepsy West syndrome alopecia anxiety disorder cocaine abuse Cushing syndrome melancholia substance withdrawal syndrome cocaine dependence hyperaldosteronism pituitary apoplexy status epilepticus Alzheimer disease Pain stereotypic movement disorder visual epilepsy West syndrome alopecia anxiety disorder cocaine abuse Cushing syndrome melancholia substance withdrawal syndrome cocaine dependence hyperaldosteronism retinitis neuroretinitis endogenous depression Spasmus nutans bipolar disorder Pick disease major depressive disorder alcohol abuse medulloblastoma mood disorder developmental and epileptic encephalopathy androgenetic alopecia neurotic disorder oligodendroglioma atypical teratoid rhabdoid tumor substance abuse glioblastoma pilocytic astrocytoma hypotensive disorder malignant ependymoma alcohol dependence depressive disorder schizophrenia dysthymic disorder astrocytic tumor osteosarcoma autosomal dominant nocturnal frontal lobe epilepsy primitive neuroectodermal tumor large cell medulloblastoma malignant glioma movement disorder Down syndrome
A, B	Pharos: P34998	major depressive disorder Pain, Postoperative cocaine abuse contact dermatitis cocaine dependence anxiety disorder depressive disorder glioblastoma atypical teratoid rhabdoid tumor breast carcinoma psoriasis malignant ependymoma bipolar disorder pilocytic astrocytoma cancer major depressive disorder Pain, Postoperative cocaine abuse contact dermatitis cocaine dependence anxiety disorder depressive disorder glioblastoma atypical teratoid rhabdoid tumor breast carcinoma psoriasis malignant ependymoma bipolar disorder pilocytic astrocytoma cancer endogenous depression idiopathic pulmonary fibrosis androgenetic alopecia large cell medulloblastoma malignant glioma mood disorder osteoarthritis, hip breast cancer primitive neuroectodermal tumor chronic obstructive pulmonary disease

Protein Modification Annotation

Modified Residue(s)
Chain	Residue(s)	Description
C, D	NH2	RESID: AA0081 , AA0083 , AA0084 , AA0086 , AA0087 , AA0088 , AA0090 , AA0091 , AA0092 , AA0093 , AA0095 , AA0096 , AA0097 , AA0098 , AA0099 , AA0100 PSI-MOD : L-alanine amide MOD:00090 , L-asparagine amide MOD:00092 , L-aspartic acid 1-amide MOD:00093 , L-glutamine amide MOD:00095 , L-glutamic acid 1-amide MOD:00096 , glycine amide MOD:00097 , L-isoleucine amide MOD:00099 , L-leucine amide MOD:00100 , L-lysine amide MOD:00101 , L-methionine amide MOD:00102 , L-proline amide MOD:00104 , L-serine amide MOD:00105 , L-threonine amide MOD:00106 , L-tryptophan amide MOD:00107 , L-tyrosine amide MOD:00108 , L-valine amide MOD:00109

RCSB PDB Core Operations are funded by the National Science Foundation (DBI-1832184), the US Department of Energy (DE-SC0019749), and the National Cancer Institute, National Institute of Allergy and Infectious Diseases, and National Institute of General Medical Sciences of the National Institutes of Health under grant R01GM133198.