3K5C

Human BACE-1 complex with NB-216

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.12 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.202 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history. 


Literature

Macrocyclic BACE-1 inhibitors acutely reduce Abeta in brain after po application.

Lerchner, A., Machauer, R., Betschart, C., Veenstra, S., Rueeger, H., McCarthy, C., Tintelnot-Blomley, M., Jaton, A.L., Rabe, S., Desrayaud, S., Enz, A., Staufenbiel, M., Paganetti, P., Rondeau, J.M., Neumann, U.

(2010) Bioorg Med Chem Lett 20: 603-607

  • DOI: https://doi.org/10.1016/j.bmcl.2009.11.092
  • Primary Citation of Related Structures:  
    3K5C

  • PubMed Abstract: 

    A series of macrocyclic peptidic BACE-1 inhibitors was designed. While potency on BACE-1 was rather high, the first set of compounds showed poor brain permeation and high efflux in the MDRI-MDCK assay. The replacement of the secondary benzylamino group with a phenylcyclopropylamino group maintained potency on BACE-1, while P-glycoprotein-mediated efflux was significantly reduced and brain permeation improved. Several compounds from this series demonstrated acute reduction of Abeta in human APP-wildtype transgenic (APP51/16) mice after oral administration.

    • Organizational Affiliation: 

    Novartis Institutes for BioMedicalResearch, Novartis Pharma AG, PO Box, CH 4002, Basel, Switzerland. [email protected]


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1
A, B, C
402Homo sapiensMutation(s): 0 
Gene Names: BACE, BACE1, KIAA1149
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
0BI
Query on 0BI
Download Ideal Coordinates CCD File 
D [auth A],
E [auth B],
F [auth C]		(4S)-4-[(1R)-1-hydroxy-2-({1-[3-(1-methylethyl)phenyl]cyclopropyl}amino)ethyl]-19-(methoxymethyl)-11-oxa-3,16-diazatric yclo[15.3.1.1~6,10~]docosa-1(21),6(22),7,9,17,19-hexaen-2-one
C35 H45 N3 O4
GCZHKZTYTMTFGU-JHOUSYSJSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0BI PDBBind:  3K5C IC50: 17 (nM) from 1 assay(s)
BindingDB:  3K5C IC50: min: 17, max: 20 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.12 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.202 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 81.752α = 90
b = 103.186β = 104.44
c = 100.144γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
CNSrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
CNXphasing
CNXrefinement

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-03-02
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary, Version format compliance
  • Version 1.2: 2017-11-01
    Changes: Refinement description
  • Version 1.3: 2024-10-30
    Changes: Data collection, Database references, Derived calculations, Structure summary