1TQF

Crystal structure of human Beta secretase complexed with inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.221 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Identification of a small molecule nonpeptide active site beta-secretase inhibitor that displays a nontraditional binding mode for aspartyl proteases.

Coburn, C.A.Stachel, S.J.Li, Y.M.Rush, D.M.Steele, T.G.Chen-Dodson, E.Holloway, M.K.Xu, M.Huang, Q.Lai, M.T.DiMuzio, J.Crouthamel, M.C.Shi, X.P.Sardana, V.Chen, Z.Munshi, S.Kuo, L.Makara, G.M.Annis, D.A.Tadikonda, P.K.Nash, H.M.Vacca, J.P.Wang, T.

(2004) J Med Chem 47: 6117-6119

  • DOI: https://doi.org/10.1021/jm049388p
  • Primary Citation of Related Structures:  
    1TQF

  • PubMed Abstract: 

    A small molecule nonpeptide inhibitor of beta-secretase has been developed, and its binding has been defined through crystallographic determination of the enzyme-inhibitor complex. The molecule is shown to bind to the catalytic aspartate residues in an unprecedented manner in the field of aspartyl protease inhibition. Additionally, the complex reveals a heretofore unknown S(3) subpocket that is created by the inhibitor. This structure has served an important role in the design of newer beta-secretase inhibitors.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Merck Research Laoratories, West Point, PA 19486-0004, USA. craig_coburn@merck.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1405Homo sapiensMutation(s): 2 
Gene Names: BACE1BACE
EC: 3.4.23.46
UniProt & NIH Common Fund Data Resources
Find proteins for P56817 (Homo sapiens)
Explore P56817 
Go to UniProtKB:  P56817
PHAROS:  P56817
GTEx:  ENSG00000186318 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP56817
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
32P
Query on 32P

Download Ideal Coordinates CCD File 
B [auth A]3-{2-[(5-AMINOPENTYL)AMINO]-2-OXOETHOXY}-5-({[1-(4-FLUOROPHENYL)ETHYL]AMINO}CARBONYL)PHENYL PHENYLMETHANESULFONATE
C29 H34 F N3 O6 S
UUMRCVIXZFKZAU-OAQYLSRUSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
32P PDBBind:  1TQF IC50: 1400 (nM) from 1 assay(s)
BindingDB:  1TQF IC50: 1400 (nM) from 1 assay(s)
Binding MOAD:  1TQF IC50: 1400 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.221 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 104.916α = 90
b = 128.181β = 90
c = 76.272γ = 90
Software Package:
Software NamePurpose
CNXrefinement
HKL-2000data reduction
SCALEPACKdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-11-09
    Type: Initial release
  • Version 1.1: 2007-10-11
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2021-10-27
    Changes: Database references, Derived calculations
  • Version 1.4: 2023-08-23
    Changes: Data collection, Refinement description