2PH8

Crystal Structure of Human Beta Secretase Complexed with inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.186 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Strategies toward improving the brain penetration of macrocyclic tertiary carbinamine BACE-1 inhibitors.

Moore, K.P.Zhu, H.Rajapakse, H.A.McGaughey, G.B.Colussi, D.Price, E.A.Sankaranarayanan, S.Simon, A.J.Pudvah, N.T.Hochman, J.H.Allison, T.Munshi, S.K.Graham, S.L.Vacca, J.P.Nantermet, P.G.

(2007) Bioorg Med Chem Lett 17: 5831-5835

  • DOI: https://doi.org/10.1016/j.bmcl.2007.08.040
  • Primary Citation of Related Structures:  
    2PH8, 2QZK

  • PubMed Abstract: 

    This letter describes replacements for the P3 amide moiety present in previously reported tertiary carbinamine macrolactones. Although P-gp efflux issues associated with these amide-macrolactones were solved and full brain penetration was measured in one case, potency was compromised in the process.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. keith_moore2@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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
35A
Query on 35A

Download Ideal Coordinates CCD File 
D [auth A]N-[(5R,14R)-5-AMINO-5,14-DIMETHYL-4-OXO-3-OXA-18-AZATRICYCLO[15.3.1.1~7,11~]DOCOSA-1(21),7(22),8,10,17,19-HEXAEN-19-YL]-N-METHYLMETHANESULFONAMIDE
C24 H33 N3 O4 S
QWDOKZPZLWNULU-MZNJEOGPSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
35A Binding MOAD:  2PH8 IC50: 1800 (nM) from 1 assay(s)
PDBBind:  2PH8 IC50: 1800 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.186 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 103.811α = 90
b = 128.523β = 90
c = 76.276γ = 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: 2008-04-22 
  • Deposition Author(s): Munshi, S.

Revision History  (Full details and data files)

  • Version 1.0: 2008-04-22
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.3: 2023-08-30
    Changes: Data collection, Refinement description