3UQR

Crystal structure of BACE1 with its inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.06 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.194 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Cyanobacterial Peptides as a Prototype for the Design of Potent beta-Secretase Inhibitors and the Development of Selective Chemical Probes for Other Aspartic Proteases

Liu, Y.Zhang, W.Li, L.Salvador, L.A.Chen, T.T.Chen, W.Y.Felsenstein, K.M.Ladd, T.B.Price, A.R.Golde, T.E.He, J.Xu, Y.C.Li, Y.Luesch, H.

(2012) J Med Chem 55: 10749-10765

  • DOI: https://doi.org/10.1021/jm301630s
  • Primary Citation of Related Structures:  
    3UQP, 3UQR, 4DV9, 4DVF, 4FGX

  • PubMed Abstract: 

    Inspired by marine cyanobacterial natural products, we synthesized modified peptides with a central statine-core unit, characteristic for aspartic protease inhibition. A series of tasiamide B analogues inhibited BACE1, a therapeutic target in Alzheimer's disease. We probed the stereospecificity of target engagement and determined additional structure-activity relationships with respect to BACE1 and related aspartic proteases, cathepsins D and E. We cocrystallized selected inhibitors with BACE1 to reveal the structural basis for the activity. Hybrid molecules that combine features of tasiamide B and an isophthalic acid moiety-containing sulfonamide showed nanomolar cellular activity. Compounds were screened in a series of rigorous complementary cell-based assays. We measured secreted APP ectodomain (sAPPβ), membrane bound carboxyl terminal fragment (CTF), levels of β-amyloid (Aβ) peptides and selectivity for β-secretase (BACE1) over γ-secretase. Prioritized compounds showed reasonable stability in vitro and in vivo, and our most potent inhibitor showed efficacy in reducing Aβ levels in the rodent brain.


  • Organizational Affiliation

    Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1
A, B, C
433Homo sapiensMutation(s): 0 
Gene Names: BACE1
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
METHYL (2S)-1-[(2R,5S,8S,12S,13S)-2,13-DIBENZYL-12-HYDROXY-3,5-DIMETHYL-15-(3-[METHYL(METHYLSULFONYL)AMINO]-5-{[(1R)-1-PHENYLETHYL]CARBAMOYL}PHENYL)-8-(2-METHYLPROPYL)-4,7,10,15-TETRAOXO-3,6,9,14-TETRAAZAPENTADECAN-1-OYL]PYRROLIDINE-2-CARBOXYLATE
D, E, F
7synthetic constructMutation(s): 0 
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
PLJ
Query on PLJ
D, E, F
L-PEPTIDE LINKINGC6 H11 N O2PRO
PSA
Query on PSA
D, E, F
PEPTIDE-LIKEC11 H15 N O3PHE
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.06 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.194 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 107.514α = 90
b = 132.121β = 90
c = 163.393γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
ADSCdata collection
MOSFLMdata reduction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-11-21
    Type: Initial release
  • Version 1.1: 2013-01-16
    Changes: Database references
  • Version 1.2: 2021-09-15
    Changes: Database references, Derived calculations, Source and taxonomy
  • Version 1.3: 2023-11-08
    Changes: Data collection, Refinement description
  • Version 1.4: 2023-12-06
    Changes: Data collection, Derived calculations