2PH6

Crystal Structure of Human Beta Secretase Complexed with inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.195 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Design, synthesis, and SAR of macrocyclic tertiary carbinamine BACE-1 inhibitors.

Lindsley, S.R.Moore, K.P.Rajapakse, H.A.Selnick, H.G.Young, M.B.Zhu, H.Munshi, S.Kuo, L.McGaughey, G.B.Colussi, D.Crouthamel, M.C.Lai, M.T.Pietrak, B.Price, E.A.Sankaranarayanan, S.Simon, A.J.Seabrook, G.R.Hazuda, D.J.Pudvah, N.T.Hochman, J.H.Graham, S.L.Vacca, J.P.Nantermet, P.G.

(2007) Bioorg Med Chem Lett 17: 4057-4061

  • DOI: https://doi.org/10.1016/j.bmcl.2007.04.072
  • Primary Citation of Related Structures:  
    2PH6

  • PubMed Abstract: 

    This Letter describes the design and synthesis of tertiary carbinamine macrocyclic inhibitors of the beta-secretase (BACE-1) enzyme. These macrocyclic inhibitors, some of which incorporate novel P2 substituents, display a 2- to 100-fold increase in potency relative to the previously described acyclic analogs while affording greater stability.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA.


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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
712
Query on 712

Download Ideal Coordinates CCD File 
C [auth A]3-({[(1R)-1-(4-FLUOROPHENYL)ETHYL]AMINO}CARBONYL)-5-[METHYL(METHYLSULFONYL)AMINO]BENZYL ALPHA-METHYL-D-PHENYLALANINATE
C28 H32 F N3 O5 S
PTQRJCCBUDSHTQ-WHLCRQNOSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
B [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
712 BindingDB:  2PH6 IC50: min: 19, max: 163 (nM) from 3 assay(s)
Binding MOAD:  2PH6 IC50: 27 (nM) from 1 assay(s)
PDBBind:  2PH6 IC50: 27 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.195 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 103.795α = 90
b = 127.13β = 90
c = 76.205γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2007-06-05 
  • Deposition Author(s): Munshi, S.

Revision History  (Full details and data files)

  • Version 1.0: 2007-06-05
    Type: Initial release
  • Version 1.1: 2007-10-10
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.4: 2023-08-30
    Changes: Data collection, Refinement description