1YM4

Crystal structure of human beta secretase complexed with NVP-AMK640


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.25 Å
  • R-Value Free: 0.288 
  • R-Value Work: 0.240 
  • R-Value Observed: 0.245 

wwPDB Validation   3D Report Full Report


This is version 2.0 of the entry. See complete history


Literature

Structure-based design, synthesis, and memapsin 2 (BACE) inhibitory activity of carbocyclic and heterocyclic peptidomimetics

Hanessian, S.Yun, H.Hou, Y.Yang, G.Bayrakdarian, M.Therrien, E.Moitessier, N.Roggo, S.Veenstra, S.Tintelnot-Blomley, M.Rondeau, J.M.Ostermeier, C.Strauss, A.Ramage, P.Paganetti, P.Neumann, U.Betschart, C.

(2005) J Med Chem 48: 5175-5190

  • DOI: https://doi.org/10.1021/jm050142+
  • Primary Citation of Related Structures:  
    1YM2, 1YM4

  • PubMed Abstract: 

    Molecular modeling based on the X-ray crystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM99-2) of BACE led to the design and synthesis of a series of constrained P(1)' analogues. A cyclopentane ring was incorporated in 1 spanning the P(1)' Ala methyl group and the adjacent methylene carbon atom of the chain. Progressive truncation at the P(2)'-P(4)' sites led to a potent truncated analogue 5 with good selectivity over Cathepsin D. Using the same backbone replacement concept, a series of cyclopentane, cyclopentanone, tetrahydrofuran, pyrrolidine, and pyrrolidinone analogues were synthesized with considerable variation at the P and P' sites. The cyclopentanone and 2-pyrrolidinone analogues 45 and 57 showed low nM BACE inhibition. X-ray cocrystal structures of two analogues 5 and 45 revealed excellent convergence with the original inhibitor 1 structure while providing new insights into other interactions which could be exploited for future modifications.


  • Organizational Affiliation

    Department of Chemistry, Université de Montréal, C. P. 6128, Succursale Centre-Ville, Montréal, Province Quebec, Canada H3C 3J7. stephen.hanessian@umontreal.ca


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1
A, B, C
408Homo sapiensMutation(s): 0 
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
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
NVP-AMK640 INHIBITORD [auth X],
E [auth Y],
F [auth Z]
5N/AMutation(s): 0 
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.25 Å
  • R-Value Free: 0.288 
  • R-Value Work: 0.240 
  • R-Value Observed: 0.245 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 223.678α = 90
b = 107.751β = 100.32
c = 61.475γ = 90
Software Package:
Software NamePurpose
CNXrefinement
DENZOdata reduction
SCALEPACKdata scaling
CNXphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-01-17
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary, Version format compliance
  • Version 1.3: 2012-12-12
    Changes: Other
  • Version 2.0: 2023-11-15
    Changes: Atomic model, Data collection, Database references, Derived calculations