5G53

Structure of the adenosine A2A receptor bound to an engineered G protein

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
Membrane Protein Annotation: OPM
Membrane Protein Annotation: PDBTM
Membrane Protein Annotation: MemProtMD
Membrane Protein Annotation: mpstruc

Domain Annotation: SCOP2 Classification SCOP2 Database Homepage

Chains	Type	Family Name	Domain Identifier	Family Identifier	Provenance Source (Version)
A	SCOP2B Superfamily	G protein-coupled receptor-like	8091190	3000473	SCOP2B (2022-06-29)
B	SCOP2B Superfamily	G protein-coupled receptor-like	8091190	3000473	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	PF00001	e5g53A1	A: alpha bundles	X: Family A G protein-coupled receptor-like (From Topology)	H: Family A G protein-coupled receptor-like (From Topology)	T: Family A G protein-coupled receptor-like	F: PF00001	ECOD (1.6)
B	PF00001	e5g53B1	A: alpha bundles	X: Family A G protein-coupled receptor-like (From Topology)	H: Family A G protein-coupled receptor-like (From Topology)	T: Family A G protein-coupled receptor-like	F: PF00001	ECOD (1.6)
C	PF00503	e5g53C1	A: a/b three-layered sandwiches	X: P-loop domains-like	H: P-loop domains-related	T: P-loop containing nucleoside triphosphate hydrolases	F: PF00503	ECOD (1.6)
D	PF00503	e5g53D1	A: a/b three-layered sandwiches	X: P-loop domains-like	H: P-loop domains-related	T: P-loop containing nucleoside triphosphate hydrolases	F: PF00503	ECOD (1.6)

Domain Annotation: CATH CATH Database Homepage

Chain	Domain	Class	Architecture	Topology	Homology	Provenance Source (Version)
A	1.20.1070.10	Mainly Alpha	Up-down Bundle	Rhopdopsin 7-helix transmembrane proteins	Rhodopsin 7-helix transmembrane proteins	CATH (4.3.0)
B	1.20.1070.10	Mainly Alpha	Up-down Bundle	Rhopdopsin 7-helix transmembrane proteins	Rhodopsin 7-helix transmembrane proteins	CATH (4.3.0)
C	3.40.50.300	Alpha Beta	3-Layer(aba) Sandwich	Rossmann fold	P-loop containing nucleotide triphosphate hydrolases	CATH (4.3.0)
D	3.40.50.300	Alpha Beta	3-Layer(aba) Sandwich	Rossmann fold	P-loop containing nucleotide triphosphate hydrolases	CATH (4.3.0)

Protein Family Annotation Pfam Database Homepage

Chains	Accession	Name	Description	Comments	Source
A, B	PF00001	7 transmembrane receptor (rhodopsin family) (7tm_1)	7 transmembrane receptor (rhodopsin family)	-	Family
C, D	PF00503	G-protein alpha subunit (G-alpha)	G-protein alpha subunit	G proteins couple receptors of extracellular signals to intracellular signaling pathways. The G protein alpha subunit binds guanyl nucleotide and is a weak GTPase. A set of residues that are unique to G-alpha as compared to its ancestor the Arf-like ...	G proteins couple receptors of extracellular signals to intracellular signaling pathways. The G protein alpha subunit binds guanyl nucleotide and is a weak GTPase. A set of residues that are unique to G-alpha as compared to its ancestor the Arf-like family form a ring of residues centered on the nucleotide binding site [3]. A Ggamma is found fused to an inactive Galpha in the Dictyostelium protein gbqA [3].	Domain

Gene Ontology: Gene Product Annotation Gene Ontology Database Homepage

Chains	Polymer	Molecular Function	Biological Process	Cellular Component
A, B	ADENOSINE RECEPTOR A2A	molecular transducer activity G protein-coupled receptor activity transmembrane signaling receptor activity signaling receptor activity G protein-coupled adenosine receptor activity protein-containing complex binding binding protein binding calmodulin binding identical protein binding cytoskeletal protein binding alpha-actinin binding actinin binding lipid binding molecular transducer activity G protein-coupled receptor activity transmembrane signaling receptor activity signaling receptor activity G protein-coupled adenosine receptor activity protein-containing complex binding binding protein binding calmodulin binding identical protein binding cytoskeletal protein binding alpha-actinin binding actinin binding lipid binding type 5 metabotropic glutamate receptor binding signaling receptor binding glutamate receptor binding G protein-coupled receptor binding G protein-coupled glutamate receptor binding enzyme binding	response to stimulus response to chemical response to xenobiotic stimulus multicellular organismal process regulation of body fluid levels wound healing hemostasis biological regulation blood coagulation response to stress coagulation regulation of biological quality response to wounding regulation of cellular process response to stimulus response to chemical response to xenobiotic stimulus multicellular organismal process regulation of body fluid levels wound healing hemostasis biological regulation blood coagulation response to stress coagulation regulation of biological quality response to wounding regulation of cellular process regulation of alpha-beta T cell activation regulation of leukocyte activation negative regulation of biological process regulation of cell activation lymphocyte activation negative regulation of lymphocyte activation leukocyte cell-cell adhesion negative regulation of cell adhesion leukocyte activation cell adhesion cell-cell adhesion T cell activation negative regulation of cellular process alpha-beta T cell activation regulation of multicellular organismal process regulation of immune system process regulation of cell-cell adhesion regulation of biological process regulation of cell adhesion cell activation regulation of T cell activation negative regulation of cell activation negative regulation of T cell activation negative regulation of immune system process negative regulation of leukocyte cell-cell adhesion immune system process negative regulation of cell-cell adhesion regulation of leukocyte cell-cell adhesion cellular process negative regulation of alpha-beta T cell activation negative regulation of multicellular organismal process negative regulation of leukocyte activation regulation of lymphocyte activation response to inorganic substance developmental process multicellular organism development central nervous system development anatomical structure development nervous system development system development trans-synaptic signaling regulation of signaling modulation of chemical synaptic transmission signaling cell-cell signaling presynaptic modulation of chemical synaptic transmission chemical synaptic transmission cell communication synaptic signaling regulation of trans-synaptic signaling anterograde trans-synaptic signaling regulation of cell communication cellular response to stimulus positive regulation of cell communication positive regulation of signal transduction positive regulation of biological process regulation of signal transduction regulation of programmed cell death positive regulation of apoptotic signaling pathway positive regulation of response to stimulus signal transduction positive regulation of cellular process positive regulation of programmed cell death regulation of apoptotic process cell death positive regulation of apoptotic process apoptotic signaling pathway regulation of response to stimulus apoptotic process programmed cell death positive regulation of signaling regulation of apoptotic signaling pathway regulation of calcium ion transport regulation of localization transport regulation of transport regulation of monoatomic ion transport establishment of localization metal ion transport calcium ion transport localization monoatomic ion transport regulation of metal ion transport monoatomic cation transport import into cell phagocytosis endocytosis vesicle-mediated transport response to organic substance response to organonitrogen compound response to nitrogen compound response to purine-containing compound response to organic cyclic compound response to caffeine response to alkaloid purinergic nucleotide receptor signaling pathway cell surface receptor signaling pathway G protein-coupled purinergic receptor signaling pathway G protein-coupled receptor signaling pathway G protein-coupled adenosine receptor signaling pathway system process sensory perception nervous system process negative regulation of vascular permeability regulation of vascular permeability circulatory system process vascular process in circulatory system blood circulation startle response regulation of response to external stimulus neuromuscular process negative regulation of response to stimulus prepulse inhibition response to external stimulus negative regulation of response to external stimulus nitrogen compound transport positive regulation of neurotransmitter secretion positive regulation of amine transport acetylcholine secretion, neurotransmission establishment of localization in cell positive regulation of acetylcholine secretion, neurotransmission positive regulation of neurotransmitter transport positive regulation of synaptic transmission, cholinergic neurotransmitter secretion organic substance transport positive regulation of synaptic transmission regulation of acetylcholine secretion, neurotransmission neurotransmitter transport organic cation transport acetate ester transport regulation of secretion signal release from synapse acetylcholine transport cellular localization positive regulation of secretion by cell regulation of secretion by cell secretion by cell positive regulation of secretion signal release acetylcholine secretion secretion regulation of neurotransmitter transport export from cell amine transport positive regulation of transport regulation of neurotransmitter secretion synaptic transmission, cholinergic regulation of amine transport regulation of synaptic transmission, cholinergic cellular biosynthetic process RNA metabolic process regulation of primary metabolic process nucleobase-containing compound metabolic process RNA biosynthetic process nucleic acid biosynthetic process DNA-templated transcription regulation of RNA metabolic process organic substance metabolic process organic substance biosynthetic process regulation of nucleobase-containing compound metabolic process regulation of RNA biosynthetic process regulation of biosynthetic process cellular metabolic process primary metabolic process regulation of cellular metabolic process regulation of macromolecule metabolic process nucleobase-containing compound biosynthetic process gene expression macromolecule biosynthetic process nucleic acid metabolic process regulation of cellular biosynthetic process organic cyclic compound metabolic process regulation of gene expression biosynthetic process organic cyclic compound biosynthetic process metabolic process regulation of macromolecule biosynthetic process regulation of DNA-templated transcription macromolecule metabolic process regulation of metabolic process cellular developmental process astrocyte differentiation cell development astrocyte activation glial cell development neurogenesis astrocyte development gliogenesis cell differentiation defense response glial cell differentiation glial cell activation inflammatory response neuroinflammatory response synaptic transmission, dopaminergic regulation of postsynaptic membrane potential chemical synaptic transmission, postsynaptic inhibitory postsynaptic potential regulation of membrane potential cellular defense response behavior locomotory behavior long-term synaptic potentiation positive regulation of long-term synaptic potentiation regulation of synaptic plasticity regulation of long-term synaptic potentiation synaptic transmission, glutamatergic regulation of synaptic transmission, glutamatergic positive regulation of synaptic transmission, glutamatergic regulation of mitochondrial membrane potential positive regulation of synaptic transmission, GABAergic synaptic transmission, GABAergic regulation of synaptic transmission, GABAergic regulation of defense response negative regulation of inflammatory response regulation of inflammatory response regulation of response to stress negative regulation of defense response renal system process positive regulation of urine volume regulation of urine volume protein kinase C-activating G protein-coupled receptor signaling pathway eating behavior feeding behavior adenylate cyclase-modulating G protein-coupled receptor signaling pathway rhythmic process circadian sleep/wake cycle, sleep circadian sleep/wake cycle rhythmic behavior regulation of circadian sleep/wake cycle circadian rhythm regulation of circadian rhythm regulation of behavior circadian behavior positive regulation of behavior positive regulation of circadian rhythm positive regulation of multicellular organismal process sleep positive regulation of circadian sleep/wake cycle, sleep regulation of circadian sleep/wake cycle, sleep circadian sleep/wake cycle process monoamine transport regulation of catecholamine secretion organic hydroxy compound transport catecholamine transport norepinephrine transport catecholamine secretion norepinephrine secretion regulation of norepinephrine secretion neuron apoptotic process negative regulation of neuron apoptotic process negative regulation of programmed cell death negative regulation of apoptotic process regulation of neuron apoptotic process cell projection organization plasma membrane bounded cell projection morphogenesis neuron projection development cell morphogenesis cellular component organization cell projection morphogenesis neuron differentiation neuron projection morphogenesis cellular component organization or biogenesis plasma membrane bounded cell projection organization generation of neurons anatomical structure morphogenesis neuron development adenylate cyclase-activating G protein-coupled receptor signaling pathway regulation of tube diameter regulation of tube size blood vessel diameter maintenance vasodilation regulation of anatomical structure size excitatory postsynaptic potential protein localization establishment of protein localization regulation of protein localization positive regulation of establishment of protein localization protein localization to extracellular region positive regulation of protein transport cellular macromolecule localization regulation of establishment of protein localization establishment of protein localization to extracellular region regulation of protein transport protein secretion positive regulation of protein secretion regulation of protein secretion protein transport regulation of cellular localization macromolecule localization positive regulation of protein localization negative regulation of cell population proliferation cell population proliferation regulation of cell population proliferation response to amine response to amphetamine membrane depolarization regulation of glutamate secretion regulation of amino acid transport glutamate secretion organic anion transport carboxylic acid transport positive regulation of glutamate secretion positive regulation of organic acid transport organic acid transport amino acid transport acidic amino acid transport positive regulation of amino acid transport regulation of organic acid transport dicarboxylic acid transport	cell periphery postsynapse postsynaptic membrane synapse cell junction membrane plasma membrane plasma membrane region cellular anatomical entity synaptic membrane presynapse presynaptic active zone presynaptic membrane somatodendritic compartment cell periphery postsynapse postsynaptic membrane synapse cell junction membrane plasma membrane plasma membrane region cellular anatomical entity synaptic membrane presynapse presynaptic active zone presynaptic membrane somatodendritic compartment cell projection dendrite dendritic tree neuron projection plasma membrane bounded cell projection glutamatergic synapse axon cell leading edge axolemma leading edge membrane neuron projection membrane main axon cell projection membrane cell body neuronal cell body polymeric cytoskeletal fiber intracellular anatomical structure intermediate filament cytoskeleton intracellular organelle cytoskeleton organelle intracellular non-membrane-bounded organelle intermediate filament supramolecular fiber supramolecular polymer supramolecular complex non-membrane-bounded organelle neuron to neuron synapse asymmetric synapse
C, D	ENGINEERED DOMAIN OF HUMAN G ALPHA S LONG ISOFORM	binding guanyl nucleotide binding GTP binding nucleotide binding guanyl ribonucleotide binding purine ribonucleotide binding purine ribonucleoside triphosphate binding nucleoside phosphate binding ion binding organic cyclic compound binding purine nucleotide binding anion binding heterocyclic compound binding carbohydrate derivative binding binding guanyl nucleotide binding GTP binding nucleotide binding guanyl ribonucleotide binding purine ribonucleotide binding purine ribonucleoside triphosphate binding nucleoside phosphate binding ion binding organic cyclic compound binding purine nucleotide binding anion binding heterocyclic compound binding carbohydrate derivative binding ribonucleotide binding small molecule binding D1 dopamine receptor binding protein binding signaling receptor binding G protein-coupled receptor binding dopamine receptor binding protein-containing complex binding G-protein beta/gamma-subunit complex binding enzyme regulator activity cyclase regulator activity enzyme activator activity cyclase activator activity molecular function activator activity molecular function regulator activity adenylate cyclase regulator activity adenylate cyclase activator activity cation binding metal ion binding pyrophosphatase activity GTPase activity ribonucleoside triphosphate phosphatase activity hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides hydrolase activity hydrolase activity, acting on acid anhydrides catalytic activity	developmental process multicellular organismal process epithelium development ectodermal placode morphogenesis epidermis development molting cycle process hair cycle animal organ development hair follicle placode formation tissue development ectodermal placode formation anatomical structure morphogenesis skin development skin epidermis development hair follicle development developmental process multicellular organismal process epithelium development ectodermal placode morphogenesis epidermis development molting cycle process hair cycle animal organ development hair follicle placode formation tissue development ectodermal placode formation anatomical structure morphogenesis skin development skin epidermis development hair follicle development molting cycle anatomical structure development anatomical structure formation involved in morphogenesis ectodermal placode development hair cycle process system process sensory perception of chemical stimulus sensory perception nervous system process sensory perception of smell positive regulation of molecular function regulation of molecular function positive regulation of hydrolase activity regulation of catalytic activity regulation of hydrolase activity biological regulation positive regulation of catalytic activity regulation of GTPase activity positive regulation of GTPase activity multicellular organism development skeletal system development bone development system development cellular response to stimulus positive regulation of cell communication regulation of cellular process positive regulation of signal transduction response to stimulus signaling positive regulation of biological process 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 positive regulation of cellular process regulation of biological process regulation of signaling positive regulation of intracellular signal transduction positive regulation of cAMP-mediated signaling regulation of response to stimulus regulation of cell communication cellular process regulation of cAMP-mediated signaling positive regulation of signaling regulation of body fluid levels wound healing homotypic cell-cell adhesion cell activation hemostasis platelet aggregation blood coagulation cell adhesion cell-cell adhesion response to stress coagulation regulation of biological quality response to wounding platelet activation cognition developmental growth growth response to organic substance response to ketone response to prostaglandin response to lipid cellular response to endogenous stimulus response to hormone response to prostaglandin E cellular response to organic substance cellular response to ketone cellular response to hormone stimulus response to endogenous stimulus response to alcohol cellular response to prostaglandin stimulus response to oxygen-containing compound cellular response to oxygen-containing compound cellular response to prostaglandin E stimulus cellular response to chemical stimulus cellular response to alcohol response to chemical cellular response to lipid adenylate cyclase-activating G protein-coupled receptor signaling pathway adenylate cyclase-modulating G protein-coupled receptor signaling pathway G protein-coupled receptor signaling pathway homeostatic process adaptive thermogenesis positive regulation of metabolic process multicellular organismal-level homeostasis regulation of cold-induced thermogenesis cold-induced thermogenesis temperature homeostasis positive regulation of cold-induced thermogenesis positive regulation of multicellular organismal process metabolic process regulation of multicellular organismal process regulation of metabolic process adenylate cyclase-activating adrenergic receptor signaling pathway adrenergic receptor signaling pathway localization cellular localization transport establishment of localization in cell intracellular transport establishment of localization positive regulation of adenylate cyclase activity positive regulation of cyclase activity regulation of lyase activity activation of adenylate cyclase activity regulation of adenylate cyclase activity regulation of cyclase activity positive regulation of lyase activity cellular response to nitrogen compound response to dopamine dopamine receptor signaling pathway cellular response to dopamine response to monoamine response to catecholamine adenylate cyclase-activating dopamine receptor signaling pathway cellular response to catecholamine stimulus response to organic cyclic compound response to organonitrogen compound cellular response to organic cyclic compound response to nitrogen compound cellular response to organonitrogen compound cellular response to monoamine stimulus	membrane cellular anatomical entity protein-containing complex extrinsic component of plasma membrane catalytic complex plasma membrane protein complex cytoplasmic side of membrane plasma membrane membrane protein complex heterotrimeric G-protein complex side of membrane cell periphery cytoplasmic side of plasma membrane GTPase complex membrane cellular anatomical entity protein-containing complex extrinsic component of plasma membrane catalytic complex plasma membrane protein complex cytoplasmic side of membrane plasma membrane membrane protein complex heterotrimeric G-protein complex side of membrane cell periphery cytoplasmic side of plasma membrane GTPase complex extrinsic component of membrane extrinsic component of cytoplasmic side of plasma membrane extracellular exosome membrane-bounded organelle extracellular vesicle extracellular organelle extracellular region organelle extracellular space vesicle extracellular membrane-bounded organelle intracellular anatomical structure cytoplasm cytosol Golgi apparatus subcompartment Golgi apparatus organelle subcompartment trans-Golgi network membrane intracellular membrane-bounded organelle endomembrane system intracellular organelle trans-Golgi network organelle membrane

InterPro: Protein Family Classification InterPro Database Homepage

Chains	Accession	Name	Type
A, B	IPR001634	Adenosine receptor	Family
A, B	IPR001513	Adenosine A2A receptor	Family
A, B	IPR000276	G protein-coupled receptor, rhodopsin-like	Family
A, B	IPR017452	GPCR, rhodopsin-like, 7TM	Domain
C, D	IPR001019	Guanine nucleotide binding protein (G-protein), alpha subunit	Family
C, D	IPR011025	G protein alpha subunit, helical insertion	Homologous Superfamily
C, D	IPR027417	P-loop containing nucleoside triphosphate hydrolase	Homologous Superfamily
C, D	IPR000367	G-protein alpha subunit, group S	Family

Pharos: Disease Associations Pharos Homepage Annotation

Chains	Drug Target	Associated Disease
A, B	Pharos: P29274	cardiomyopathy rheumatoid arthritis Sepsis panic disorder amphetamine abuse Parkinson disease substance withdrawal syndrome drug allergy visual epilepsy melancholia endogenous depression bronchitis heart disease common cold lung disease cardiomyopathy rheumatoid arthritis Sepsis panic disorder amphetamine abuse Parkinson disease substance withdrawal syndrome drug allergy visual epilepsy melancholia endogenous depression bronchitis heart disease common cold lung disease migraine disorder anxiety disorder inherited disease susceptibility acne pulmonary emphysema neurotic disorder hypotensive disorder insomnia ischemia reperfusion injury allergic rhinitis depressive disorder drug psychosis movement disorder schizophrenia asthma
C, D	Pharos: P63092	McCune-Albright syndrome progressive osseous heteroplasia pseudohypoparathyroidism type 1A pseudohypoparathyroidism polycystic ovary syndrome acromegaly pseudohypoparathyroidism type 1B cholangiocarcinoma pseudopseudohypoparathyroidism precocious puberty obesity disorder substance withdrawal syndrome pseudohypoaldosteronism ACTH-independent macronodular adrenal hyperplasia 1 neuroblastoma McCune-Albright syndrome progressive osseous heteroplasia pseudohypoparathyroidism type 1A pseudohypoparathyroidism polycystic ovary syndrome acromegaly pseudohypoparathyroidism type 1B cholangiocarcinoma pseudopseudohypoparathyroidism precocious puberty obesity disorder substance withdrawal syndrome pseudohypoaldosteronism ACTH-independent macronodular adrenal hyperplasia 1 neuroblastoma brachydactyly intellectual disability pseudohypoparathyroidism type 1C Cafe-au-Lait Spots hypertensive disorder monostotic fibrous dysplasia cancer colorectal cancer intrahepatic cholangiocarcinoma endocrine system disease autosomal dominant pseudohypoaldosteronism type 1 sex cord-stromal tumor Cushing disease due to pituitary adenoma adrenal gland cancer growth hormone-producing pituitary gland adenoma pilocytic astrocytoma tuberculosis interstitial cystitis congenital hypothyroidism large cell medulloblastoma Cushing syndrome malignant glioma acquired metabolic disease progressive supranuclear palsy medulloblastoma pseudohypoaldosteronism type 2 ductal breast carcinoma in situ adenoma adrenal gland hyperfunction osteitis fibrosa ovarian cancer atypical teratoid rhabdoid tumor pancreatic intraductal papillary-mucinous neoplasm with low grade dysplasia bile duct cancer testicular sex cord-stromal neoplasm pituitary cancer craniosynostosis Cushing syndrome due to macronodular adrenal hyperplasia fibrodysplasia ossificans progressiva oligodendroglioma gallstones osteogenesis imperfecta schizophrenia growth hormone secreting pituitary adenoma 1 pancreatic intraductal papillary-mucinous carcinoma hemorrhagic disease Pick disease pituitary gland adenoma congenital anemia invasive ductal breast carcinoma malignant ependymoma cystic fibrosis ACTH-dependent Cushing syndrome pseudohypoaldosteronism type 1 endogenous depression neurofibromatosis type 1 fibrous dysplasia Alzheimer disease glioblastoma osteosarcoma astrocytic tumor pancreatic intraductal papillary-mucinous neoplasm autosomal recessive pseudohypoaldosteronism type 1

Membrane Protein Annotation: OPM OPM Database Homepage

Chains	External Link	Type	Class	Superfamily	Family
A, B, C, D	OPM	Transmembrane	Alpha-helical polytopic	Rhodopsin-like receptors and pumps	G-protein coupled receptors, family A

Membrane Protein Annotation: PDBTM PDBTM Database Homepage

Chains	External Link	Comment
A, B, C, D	PDBTM	Annotated as membrane protein by PDBTM

Membrane Protein Annotation: MemProtMD MemProtMD Database Homepage

Chains	External Link	Comment
A, B, C, D	MemProtMD	Annotated as membrane protein by MemProtMD

Membrane Protein Annotation: mpstruc mpstruc Database Homepage

Chains	Resource Link	Group	Subgroup	Protein
A, B, C, D	mpstruc	TRANSMEMBRANE PROTEINS: ALPHA-HELICAL	G Protein-Coupled Receptors: Class A	A_2A adenosine receptor with bound engineered G protein

RCSB PDB Core Operations are funded by the U.S. National Science Foundation (DBI-2321666), 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.