5KWY

Structure of human NPC1 middle lumenal domain bound to NPC2

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

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

Chains	Domain Info	Class	Fold	Superfamily	Family	Domain	Species	Provenance Source (Version)
C	d5kwyc1	All beta proteins	Immunoglobulin-like beta-sandwich	E set domains	ML domain	automated matches	Human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
C	d5kwyc2	Artifacts	Tags	Tags	Tags	C-terminal Tags	Human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
D	d5kwyd_	All beta proteins	Immunoglobulin-like beta-sandwich	E set domains	ML domain	automated matches	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)
C	SCOP2 Family	ML domain	8083265	4007517	SCOP2 (2022-06-29)
C	SCOP2 Superfamily	E set domains	8083266	3000070	SCOP2 (2022-06-29)
D	SCOP2B Superfamily	E set domains	8083266	3000070	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)
C	E1_DerP2_DerF2	e5kwyC1	A: beta sandwiches	X: Immunoglobulin-like beta-sandwich	H: Immunoglobulin-related	T: Immunoglobulin/Fibronectin type III/E set domains/PapD-like	F: E1_DerP2_DerF2	ECOD (1.6)
D	E1_DerP2_DerF2	e5kwyD1	A: beta sandwiches	X: Immunoglobulin-like beta-sandwich	H: Immunoglobulin-related	T: Immunoglobulin/Fibronectin type III/E set domains/PapD-like	F: E1_DerP2_DerF2	ECOD (1.6)
A	2A060601	e5kwyA1	A: a+b two layers	X: Alpha-beta plaits	H: Ferredoxin domains in multidrug efflux transporter	T: Multidrug efflux transporter AcrB pore domain	F: 2A060601	ECOD (1.6)
B	2A060601	e5kwyB1	A: a+b two layers	X: Alpha-beta plaits	H: Ferredoxin domains in multidrug efflux transporter	T: Multidrug efflux transporter AcrB pore domain	F: 2A060601	ECOD (1.6)

Domain Annotation: CATH CATH Database Homepage

Chain	Domain	Class	Architecture	Topology	Homology	Provenance Source (Version)
C	2.60.40.770	Mainly Beta	Sandwich	Immunoglobulin-like		CATH (4.3.0)
D	2.60.40.770	Mainly Beta	Sandwich	Immunoglobulin-like		CATH (4.3.0)

Protein Family Annotation Pfam Database Homepage

Chains	Accession	Name	Description	Comments	Source
C, D	PF02221	ML domain (E1_DerP2_DerF2)	ML domain	ML domain - MD-2-related lipid recognition domain. This family consists of proteins from plants, animals and fungi, including dust mite allergen Der P 2 (Swiss:P49278). It has been implicate in lipid recognition, particularly in the recognition of pa ...	ML domain - MD-2-related lipid recognition domain. This family consists of proteins from plants, animals and fungi, including dust mite allergen Der P 2 (Swiss:P49278). It has been implicate in lipid recognition, particularly in the recognition of pathogen related products. A mutation in Npc2 (Swiss:Q15668) causes a rare form of Niemann-Pick type C2 disease. This domain has a similar topology to immunoglobulin domains.	Domain
A, B	PF22314	NPC1, middle luminal domain (NPC1_MLD)	NPC1, middle luminal domain	NPC intracellular cholesterol transporter 1 (NPC1) is a endosomal/lysosomal membrane protein that facilitates the trafficking of cholesterol and other cargo from lysosomes and is involved in cholesterol homeostasis. Mutations in the NPC1 gene cause t ...	NPC intracellular cholesterol transporter 1 (NPC1) is a endosomal/lysosomal membrane protein that facilitates the trafficking of cholesterol and other cargo from lysosomes and is involved in cholesterol homeostasis. Mutations in the NPC1 gene cause the rare neurodegenerative disease Niemann-Pick Type C (NPC). This entry represents the middle luminal domain (MLD) of NPC1, which contains the Ebola glycoprotein interacting site [5].	Domain

Gene Ontology: Gene Product Annotation Gene Ontology Database Homepage

Chains	Polymer	Molecular Function	Biological Process	Cellular Component
C, D	Epididymal secretory protein E1	sterol binding binding organic cyclic compound binding alcohol binding steroid binding lipid binding cholesterol binding small molecule binding sterol transfer activity lipid transporter activity lipid transfer activity transporter activity cholesterol transfer activity protein binding sterol binding binding organic cyclic compound binding alcohol binding steroid binding lipid binding cholesterol binding small molecule binding sterol transfer activity lipid transporter activity lipid transfer activity transporter activity cholesterol transfer activity protein binding enzyme binding	localization transport macromolecule localization phospholipid transport lipid localization lipid transport establishment of localization organophosphate ester transport cholesterol transport sterol transport organic hydroxy compound transport sterol homeostasis chemical homeostasis homeostatic process localization transport macromolecule localization phospholipid transport lipid localization lipid transport establishment of localization organophosphate ester transport cholesterol transport sterol transport organic hydroxy compound transport sterol homeostasis chemical homeostasis homeostatic process cholesterol homeostasis lipid homeostasis organic hydroxy compound metabolic process sterol metabolic process steroid metabolic process cholesterol metabolic process alcohol metabolic process primary metabolic process secondary alcohol metabolic process small molecule metabolic process metabolic process cellular process lipid metabolic process cellular localization intracellular lipid transport intracellular cholesterol transport intracellular transport intracellular sterol transport establishment of localization in cell cholesterol storage lipid storage maintenance of location biosynthetic process macromolecule metabolic process gene expression macromolecule biosynthetic process regulation of biological process regulation of cellular process regulation of lipid metabolic process biological regulation regulation of primary metabolic process regulation of isoprenoid metabolic process regulation of metabolic process isoprenoid metabolic process cholesterol efflux biological process involved in interspecies interaction between organisms response to stimulus response to other organism response to external stimulus response to external biotic stimulus response to virus response to biotic stimulus glycolipid transport carbohydrate derivative transport	membrane-bounded organelle intracellular anatomical structure lytic vacuole membrane-enclosed lumen vacuolar lumen vacuole intracellular membrane-bounded organelle lysosomal lumen intracellular organelle lumen intracellular organelle cellular anatomical structure organelle lumen organelle cytoplasm membrane-bounded organelle intracellular anatomical structure lytic vacuole membrane-enclosed lumen vacuolar lumen vacuole intracellular membrane-bounded organelle lysosomal lumen intracellular organelle lumen intracellular organelle cellular anatomical structure organelle lumen organelle cytoplasm lysosome extracellular exosome extracellular vesicle extracellular organelle extracellular region extracellular space vesicle extracellular membrane-bounded organelle intracellular vesicle cytoplasmic vesicle lumen endomembrane system cytoplasmic vesicle vesicle lumen azurophil granule secretory granule lumen azurophil granule lumen secretory granule primary lysosome secretory vesicle endoplasmic reticulum
A, B	Niemann-Pick C1 protein	molecular transducer activity transmembrane signaling receptor activity signaling receptor activity protein binding binding virus receptor activity exogenous protein binding sterol binding organic cyclic compound binding alcohol binding steroid binding lipid binding cholesterol binding small molecule binding molecular transducer activity transmembrane signaling receptor activity signaling receptor activity protein binding binding virus receptor activity exogenous protein binding sterol binding organic cyclic compound binding alcohol binding steroid binding lipid binding cholesterol binding small molecule binding lipid transporter activity transporter activity	response to stimulus response to chemical response to xenobiotic stimulus cellular localization intracellular lipid transport transport lipid localization lipid transport intracellular transport establishment of localization localization macromolecule localization establishment of localization in cell cellular process response to stimulus response to chemical response to xenobiotic stimulus cellular localization intracellular lipid transport transport lipid localization lipid transport intracellular transport establishment of localization localization macromolecule localization establishment of localization in cell cellular process biological process involved in interspecies interaction between organisms symbiont entry into host cell viral process symbiont entry into host viral life cycle biological process involved in interaction with host biological process involved in symbiotic interaction catabolic process autophagy metabolic process process utilizing autophagic mechanism cholesterol transport sterol transport organic hydroxy compound transport cell death programmed cell death cellular response to stimulus response to lipid response to endogenous stimulus cellular response to organic cyclic compound cellular response to endogenous stimulus cellular response to chemical stimulus response to hormone response to steroid hormone cellular response to lipid cellular response to steroid hormone stimulus response to organic cyclic compound cellular response to hormone stimulus intracellular cholesterol transport intracellular sterol transport intestinal lipid absorption multicellular organismal process digestion system process intestinal absorption digestive system process intestinal cholesterol absorption lipid digestion cellular response to low-density lipoprotein particle stimulus response to lipoprotein particle response to nitrogen compound cellular response to lipoprotein particle stimulus cholesterol efflux carbohydrate metabolic process glucan metabolic process polysaccharide metabolic process oligosaccharide metabolic process primary metabolic process macromolecule metabolic process cyclodextrin metabolic process adult walking behavior adult locomotory behavior behavior adult behavior locomotory behavior walking behavior regulation of biological process regulation of cellular process regulation of epithelial cell apoptotic process negative regulation of programmed cell death regulation of apoptotic process biological regulation negative regulation of biological process regulation of programmed cell death epithelial cell apoptotic process negative regulation of apoptotic process negative regulation of epithelial cell apoptotic process negative regulation of cellular process apoptotic process developmental process multicellular organism development hepaticobiliary system development gland development animal organ development anatomical structure development liver development system development neurogenesis cellular developmental process cell differentiation nervous system development oxoacid metabolic process steroid metabolic process organic hydroxy compound metabolic process carboxylic acid metabolic process organic acid metabolic process bile acid metabolic process small molecule metabolic process monocarboxylic acid metabolic process lipid metabolic process membrane organization cellular component organization membrane raft organization cellular component organization or biogenesis import into cell endocytosis vesicle-mediated transport negative regulation of catabolic process macroautophagy negative regulation of metabolic process regulation of catabolic process regulation of autophagy negative regulation of macroautophagy regulation of macroautophagy negative regulation of autophagy regulation of metabolic process sterol homeostasis chemical homeostasis homeostatic process cholesterol homeostasis lipid homeostasis sterol metabolic process cholesterol metabolic process alcohol metabolic process secondary alcohol metabolic process carbohydrate derivative biosynthetic process glycoprotein biosynthetic process carbohydrate derivative metabolic process glycoprotein metabolic process protein glycosylation macromolecule biosynthetic process biosynthetic process glycosylation macromolecule modification macromolecule glycosylation protein metabolic process protein modification process cholesterol storage lipid storage maintenance of location gene expression vacuolar transport lysosomal transport signaling negative regulation of signaling negative regulation of intracellular signal transduction regulation of signal transduction intracellular signal transduction negative regulation of cell communication cell communication negative regulation of TORC1 signaling regulation of intracellular signal transduction negative regulation of TOR signaling signal transduction regulation of TORC1 signaling TOR signaling regulation of signaling regulation of TOR signaling negative regulation of response to stimulus negative regulation of signal transduction regulation of response to stimulus regulation of cell communication TORC1 signaling protein localization establishment of protein localization establishment of protein localization to membrane localization within membrane protein localization to membrane cellular macromolecule localization response to metal ion response to cadmium ion	cellular anatomical structure membrane membrane-bounded organelle intracellular organelle organelle envelope intracellular anatomical structure organelle nuclear envelope nucleus intracellular membrane-bounded organelle endomembrane system extracellular exosome extracellular vesicle extracellular organelle cellular anatomical structure membrane membrane-bounded organelle intracellular organelle organelle envelope intracellular anatomical structure organelle nuclear envelope nucleus intracellular membrane-bounded organelle endomembrane system extracellular exosome extracellular vesicle extracellular organelle extracellular region extracellular space vesicle extracellular membrane-bounded organelle endosome membrane endosome intracellular vesicle late endosome membrane cytoplasmic vesicle membrane bounding membrane of organelle cytoplasmic vesicle vesicle membrane late endosome cytoplasm organelle membrane vacuolar membrane lytic vacuole vacuole lytic vacuole membrane lysosomal membrane lysosome Golgi apparatus perinuclear region of cytoplasm cell periphery plasma membrane membrane microdomain membrane raft endoplasmic reticulum

InterPro: Protein Family Classification InterPro Database Homepage

Chains	Accession	Name	Type
C, D	IPR003172	MD-2-related lipid-recognition domain	Domain
C, D	IPR033916	Npc2 like, ML domain	Domain
C, D	IPR014756	Immunoglobulin E-set	Homologous Superfamily
C, D	IPR039670	Sterol transport protein NPC2-like	Family
A, B	IPR032190	Niemann-Pick C1, N-terminal	Domain
A, B	IPR003392	Patched domain-containing protein, SSD domain	Domain
A, B	IPR004765	NPC1-like	Family
A, B	IPR000731	Sterol-sensing domain	Domain
A, B	IPR053958	HMGCR/SNAP/NPC1-like, sterol-sensing domain	Domain
A, B	IPR053956	NPC1, middle luminal domain	Domain

Pharos: Disease Associations Pharos Homepage Annotation

Chains	Drug Target	Associated Disease
C, D	Pharos: P61916	Niemann-Pick disease Niemann-Pick disease, type C2 ovarian cancer peripheral nervous system disease sphingolipidosis astrocytic tumor C syndrome Down syndrome histiocytosis intellectual disability lung cancer malignant ependymoma pancreatic intraductal papillary-mucinous carcinoma peripheral neuropathy subependymal giant cell astrocytoma Niemann-Pick disease Niemann-Pick disease, type C2 ovarian cancer peripheral nervous system disease sphingolipidosis astrocytic tumor C syndrome Down syndrome histiocytosis intellectual disability lung cancer malignant ependymoma pancreatic intraductal papillary-mucinous carcinoma peripheral neuropathy subependymal giant cell astrocytoma Ataxias, Hereditary cholestasis Duchenne muscular dystrophy large cell medulloblastoma lung carcinoma malignant glioma non-Langerhans cell histiocytosis pancreatic intraductal papillary-mucinous neoplasm pilocytic astrocytoma atypical teratoid rhabdoid tumor glioblastoma inborn errors of metabolism leukodystrophy lysosomal storage disease
A, B	Pharos: O15118	Niemann-Pick disease ophthalmoplegia Niemann-Pick disease, type C1 obesity disorder gastrointestinal stromal tumor Ataxia atherosclerosis cirrhosis of liver liver disease brucellosis osteosarcoma sphingolipidosis histiocytosis inborn errors of metabolism large cell medulloblastoma Niemann-Pick disease ophthalmoplegia Niemann-Pick disease, type C1 obesity disorder gastrointestinal stromal tumor Ataxia atherosclerosis cirrhosis of liver liver disease brucellosis osteosarcoma sphingolipidosis histiocytosis inborn errors of metabolism large cell medulloblastoma lysosomal storage disease metabolic syndrome X ovarian cancer Gaucher disease hydrops fetalis adrenal cortex carcinoma intellectual disability leukodystrophy lung cancer malignant pancreatic neoplasm C syndrome non-Langerhans cell histiocytosis psoriasis tuberculosis heart disease arteriosclerosis disorder lung carcinoma medulloblastoma Niemann-Pick disease type C cholestasis Down syndrome

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 R01GM157729.