1R1J

STRUCTURAL ANALYSIS OF NEPRILYSIN WITH VARIOUS SPECIFIC AND POTENT INHIBITORS

External Resource: Annotation

Domain Annotation: SCOP/SCOPe Classification
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
Structure Motif: Primary M-CSA Annotation

Domain Annotation: SCOP/SCOPe Classification SCOP-e Database Homepage

Chains	Domain Info	Class	Fold	Superfamily	Family	Domain	Species	Provenance Source (Version)
A	d1r1ja_	Alpha and beta proteins (a+b)	Zincin-like	Metalloproteases ('zincins'), catalytic domain	Neutral endopeptidase (neprilysin)	Neutral endopeptidase (neprilysin)	human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)

Domain Annotation: SCOP2 Classification SCOP2 Database Homepage

Chains	Type	Family Name	Domain Identifier	Family Identifier	Provenance Source (Version)
A	SCOP2B Superfamily	Metalloproteases (zincins) catalytic domain	8035463	3001975	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	PF01431,PF05649	e1r1jA1	A: mixed a+b and a/b	X: Zincin-like	H: Metalloproteases (zincins) catalytic domain (From Topology)	T: Metalloproteases (zincins) catalytic domain	F: PF01431,PF05649	ECOD (1.6)

Domain Annotation: CATH CATH Database Homepage

Chain	Domain	Class	Architecture	Topology	Homology	Provenance Source (Version)
A	3.40.390.10	Alpha Beta	3-Layer(aba) Sandwich	Collagenase (Catalytic Domain)	Collagenase (Catalytic Domain)	CATH (4.3.0)
A	1.10.1380.10	Mainly Alpha	Orthogonal Bundle	Neutral endopeptidase	domain 2	CATH (4.3.0)

Protein Family Annotation Pfam Database Homepage

Chains	Accession	Name	Description	Comments	Source
A	PF05649	Peptidase family M13 (Peptidase_M13_N)	Peptidase family M13	-	Family
A	PF01431	Peptidase family M13 (Peptidase_M13)	Peptidase family M13	-	Family

Gene Ontology: Gene Product Annotation Gene Ontology Database Homepage

Chains	Polymer	Molecular Function	Biological Process	Cellular Component
A	Neprilysin	ion binding binding anion binding phosphatidylglycerol binding phospholipid binding lipid binding cardiolipin binding small molecule binding peptidase activity catalytic activity, acting on a protein hydrolase activity catalytic activity endopeptidase activity modified amino acid binding ion binding binding anion binding phosphatidylglycerol binding phospholipid binding lipid binding cardiolipin binding small molecule binding peptidase activity catalytic activity, acting on a protein hydrolase activity catalytic activity endopeptidase activity modified amino acid binding phosphatidylserine binding metalloendopeptidase activity metallopeptidase activity identical protein binding protein binding protein homodimerization activity protein dimerization activity oligopeptidase activity exopeptidase activity peptide binding cation binding transition metal ion binding zinc ion binding metal ion binding	cellular catabolic process multicellular organismal process catabolic process amyloid-beta clearance by cellular catabolic process cellular metabolic process metabolic process cellular process amyloid-beta clearance developmental process placenta development animal organ development anatomical structure development replicative senescence organonitrogen compound catabolic process cellular catabolic process multicellular organismal process catabolic process amyloid-beta clearance by cellular catabolic process cellular metabolic process metabolic process cellular process amyloid-beta clearance developmental process placenta development animal organ development anatomical structure development replicative senescence organonitrogen compound catabolic process organonitrogen compound metabolic process primary metabolic process protein catabolic process macromolecule catabolic process organic substance metabolic process protein metabolic process macromolecule metabolic process organic substance catabolic process substance P catabolic process peptide catabolic process neuropeptide catabolic process amide metabolic process peptide metabolic process creatinine metabolic process organic cyclic compound metabolic process small molecule metabolic process lactam metabolic process cellular response to stimulus response to light stimulus response to stimulus cellular response to radiation response to UV response to UV-B cellular response to environmental stimulus cellular response to UV-B cellular response to light stimulus response to radiation response to abiotic stimulus cellular response to abiotic stimulus cellular response to UV positive regulation of nervous system development regulation of cellular process regulation of developmental process cellular developmental process positive regulation of biological process cell development regulation of cell differentiation regulation of neurogenesis regulation of cell development regulation of nervous system development positive regulation of developmental process multicellular organism development neurogenesis positive regulation of cell differentiation cell differentiation positive regulation of neurogenesis regulation of multicellular organismal process positive regulation of cellular process system development regulation of multicellular organismal development regulation of biological process biological regulation positive regulation of cell development nervous system development positive regulation of multicellular organismal process bradykinin catabolic process kidney development renal system development amyloid-beta metabolic process response to organic substance response to hormone response to chemical response to endogenous stimulus response to estrogen positive regulation of cell communication modulation of chemical synaptic transmission signaling cell communication long-term synaptic potentiation synaptic signaling positive regulation of long-term synaptic potentiation regulation of biological quality regulation of synaptic plasticity trans-synaptic signaling regulation of signaling cell-cell signaling positive regulation of synaptic transmission chemical synaptic transmission regulation of trans-synaptic signaling anterograde trans-synaptic signaling regulation of long-term synaptic potentiation regulation of cell communication positive regulation of signaling tube development respiratory tube development lung development respiratory system development cellular biosynthetic process gene expression macromolecule biosynthetic process protein maturation biosynthetic process proteolysis organic substance biosynthetic process protein processing signaling receptor ligand precursor processing neuropeptide processing behavior system process learning or memory nervous system process cognition regulation of hormone levels hormone metabolic process hormone catabolic process sensory perception sensory perception of pain cellular response to UV-A response to UV-A cellular response to chemical stimulus response to cytokine cellular response to cytokine stimulus cellular response to organic substance	membrane cellular anatomical entity extracellular exosome membrane-bounded organelle extracellular vesicle extracellular organelle extracellular region organelle extracellular space vesicle extracellular membrane-bounded organelle cluster of actin-based cell projections brush border somatodendritic compartment membrane cellular anatomical entity extracellular exosome membrane-bounded organelle extracellular vesicle extracellular organelle extracellular region organelle extracellular space vesicle extracellular membrane-bounded organelle cluster of actin-based cell projections brush border somatodendritic compartment cell projection dendrite dendritic tree neuron projection plasma membrane bounded cell projection intracellular anatomical structure cytoplasm Golgi apparatus subcompartment Golgi apparatus organelle subcompartment intracellular membrane-bounded organelle endomembrane system intracellular organelle trans-Golgi network cell body neuronal cell body axon transport vesicle synapse intracellular vesicle presynapse cytoplasmic vesicle synaptic vesicle cell junction secretory vesicle exocytic vesicle anchoring junction focal adhesion cell-substrate junction cell surface cell periphery plasma membrane membrane microdomain membrane raft early endosome endosome neuron projection terminus cytoplasmic vesicle membrane bounding membrane of organelle vesicle membrane secretory granule organelle membrane secretory granule membrane

InterPro: Protein Family Classification InterPro Database Homepage

Chains	Accession	Name	Type
A	IPR018497	Peptidase M13, C-terminal domain	Domain
A	IPR008753	Peptidase M13, N-terminal domain	Domain
A	IPR000718	Peptidase M13	Family
A	IPR024079	Metallopeptidase, catalytic domain superfamily	Homologous Superfamily
A	IPR042089	Peptidase M13, domain 2	Homologous Superfamily

Pharos: Disease Associations Pharos Homepage Annotation

Chains	Drug Target	Associated Disease
A	Pharos: P08473	Charcot-Marie-Tooth disease autosomal dominant cerebellar ataxia Charcot-Marie-Tooth disease axonal type 2T breast carcinoma prostate cancer kidney failure diabetic autonomic neuropathy diabetic neuropathy Liver Cirrhosis, Experimental breast cancer cryopyrin-associated periodic syndrome peripheral neuropathy diabetic polyneuropathy spinocerebellar ataxia 43 periodontitis Charcot-Marie-Tooth disease autosomal dominant cerebellar ataxia Charcot-Marie-Tooth disease axonal type 2T breast carcinoma prostate cancer kidney failure diabetic autonomic neuropathy diabetic neuropathy Liver Cirrhosis, Experimental breast cancer cryopyrin-associated periodic syndrome peripheral neuropathy diabetic polyneuropathy spinocerebellar ataxia 43 periodontitis ductal breast carcinoma in situ spinocerebellar ataxia type 1 hereditary ataxia idiopathic membranous glomerulonephritis spinocerebellar ataxia type 5 spondyloarthropathy acute diarrhea lung cancer ulcerative colitis lymphatic system disease cancer membranous glomerulonephritis myopathy cystic fibrosis osteosarcoma peripheral nervous system disease facioscapulohumeral muscular dystrophy spinocerebellar ataxia type 2 invasive ductal breast carcinoma spinocerebellar ataxia type 6 acute myeloid leukemia lung carcinoma malignant colon neoplasm cerebellar ataxia motor peripheral neuropathy neurodegenerative disease pancreatic intraductal papillary-mucinous carcinoma familial cold autoinflammatory syndrome spinocerebellar ataxia type 4 hypertensive disorder kidney disease spinocerebellar ataxia type 7 lung adenocarcinoma transitional cell carcinoma malignant mesothelioma Muckle-Wells syndrome cutaneous lupus erythematosus non-small cell lung carcinoma

Structure Motif Annotation: Mechanism and Catalytic Site Atlas M-CSA Database Homepage

Chains	Enzyme Name	Description	Catalytic Residues
A	neprilysin M-CSA #623	Neutral endopeptidase, or neprelysin, is a Zinc protease located in the membrane of mammalian tissue and responsible for the hydrolysis of peptides such as Insulin at the cell surface. As a result it plays a key role in many of the processes involved in cell signalling. Although it displays little sequence or structural homology to other known Zinc dependent proteases such as the bacterial protein thermolysin, it's active site can be successfully aligned to the active site of thermolysin, thus convergent evolution is believed to account for the similarity in mechanism between the two that is observed.	Defined by 7 residues: HIS:A-530 [auth A-583]GLU:A-531 [auth A-584]HIS:A-534 [auth A-587]GLU:A-593 [auth A-646]ASP:A-597 [auth A-650]HIS:A-658 [auth A-711]ARG:A-664 [auth A-717] \| Explore in 3D: M-CSA Motif Definition Search M-CSA Motif EC: 3.4.24.11 (PDB Primary Data) Search M-CSA Motif + EC 3.4.24.11

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.