3GKH

NPC1(NTD)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.81 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol.

Kwon, H.J.Abi-Mosleh, L.Wang, M.L.Deisenhofer, J.Goldstein, J.L.Brown, M.S.Infante, R.E.

(2009) Cell 137: 1213-1224

  • DOI: https://doi.org/10.1016/j.cell.2009.03.049
  • Primary Citation of Related Structures:  
    3GKH, 3GKI, 3GKJ

  • PubMed Abstract: 

    LDL delivers cholesterol to lysosomes by receptor-mediated endocytosis. Exit of cholesterol from lysosomes requires two proteins, membrane-bound Niemann-Pick C1 (NPC1) and soluble NPC2. NPC2 binds cholesterol with its isooctyl side chain buried and its 3beta-hydroxyl exposed. Here, we describe high-resolution structures of the N-terminal domain (NTD) of NPC1 and complexes with cholesterol and 25-hydroxycholesterol. NPC1(NTD) binds cholesterol in an orientation opposite to NPC2: 3beta-hydroxyl buried and isooctyl side chain exposed. Cholesterol transfer from NPC2 to NPC1(NTD) requires reorientation of a helical subdomain in NPC1(NTD), enlarging the opening for cholesterol entry. NPC1 with point mutations in this subdomain (distinct from the binding subdomain) cannot accept cholesterol from NPC2 and cannot restore cholesterol exit from lysosomes in NPC1-deficient cells. We propose a working model wherein after lysosomal hydrolysis of LDL-cholesteryl esters, cholesterol binds NPC2, which transfers it to NPC1(NTD), reversing its orientation and allowing insertion of its isooctyl side chain into the outer lysosomal membranes.


  • Organizational Affiliation

    Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Niemann-Pick C1 protein232Homo sapiensMutation(s): 3 
Gene Names: NPC1
UniProt & NIH Common Fund Data Resources
Find proteins for O15118 (Homo sapiens)
Explore O15118 
Go to UniProtKB:  O15118
PHAROS:  O15118
GTEx:  ENSG00000141458 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO15118
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
B
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.81 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 
  • Space Group: P 64
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.181α = 90
b = 66.181β = 90
c = 82.644γ = 120
Software Package:
Software NamePurpose
REFMACrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2009-07-14 
  • Deposition Author(s): Kwon, H.J.

Revision History  (Full details and data files)

  • Version 1.0: 2009-07-14
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Database references, Derived calculations, Structure summary
  • Version 2.1: 2021-10-20
    Changes: Database references, Structure summary