5MCO

CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH ACTIVE SITE INHIBITOR GRL-8234 AND EXOSITE PEPTIDE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.49 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.175 

wwPDB Validation 3D Report Full Report


This is version 1.1 of the entry. See complete history

Literature

Potent and Selective BACE-1 Peptide Inhibitors Lower Brain A beta Levels Mediated by Brain Shuttle Transport.

Ruderisch, N.Schlatter, D.Kuglstatter, A.Guba, W.Huber, S.Cusulin, C.Benz, J.Rufer, A.C.Hoernschemeyer, J.Schweitzer, C.Bulau, T.Gartner, A.Hoffmann, E.Niewoehner, J.Patsch, C.Baumann, K.Loetscher, H.Kitas, E.Freskgard, P.O.

(2017) EBioMedicine 24: 76-92

  • DOI: 10.1016/j.ebiom.2017.09.004
  • Primary Citation of Related Structures:  

  • PubMed Abstract: 
  • Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidβ (Aβ) antibodies and secretase inhibitors. However, the blood-brain barrier (BBB) limits the brain exposure of biologics and the chemical space for small molecules to be BBB per ...

    Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidβ (Aβ) antibodies and secretase inhibitors. However, the blood-brain barrier (BBB) limits the brain exposure of biologics and the chemical space for small molecules to be BBB permeable. The Brain Shuttle (BS) technology is capable of shuttling large molecules into the brain. This allows for new types of therapeutic modalities engineered for optimal efficacy on the molecular target in the brain independent of brain penetrating properties. To this end, we designed BACE1 peptide inhibitors with varying lipid modifications with single-digit picomolar cellular potency. Secondly, we generated active-exosite peptides with structurally confirmed dual binding mode and improved potency. When fused to the BS via sortase coupling, these BACE1 inhibitors significantly reduced brain Aβ levels in mice after intravenous administration. In plasma, both BS and non-BS BACE1 inhibitor peptides induced a significant time- and dose-dependent decrease of Aβ. Our results demonstrate that the BS is essential for BACE1 peptide inhibitors to be efficacious in the brain and active-exosite design of BACE1 peptide inhibitors together with lipid modification may be of therapeutic relevance.


    Organizational Affiliation

    Pharma Research and Early Development (pRED), Neurodegeneration and Regeneration, Roche Innovation Center Basel, Switzerland.,Pharma Research and Early Development (pRED), Neurodegeneration and Regeneration, Roche Innovation Center Basel, Switzerland. Electronic address: per-ola.freskgard@roche.com.,Pharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Basel, Switzerland.,Pharma Research and Early Development (pRED), Therapeutic Modalities, Roche Innovation Center Munich, Germany.




Macromolecules

Find similar proteins by: Sequence  |  Structure

Entity ID: 1
MoleculeChainsSequence LengthOrganismDetails
Beta-secretase 1
A
409Homo sapiensMutation(s): 1 
Gene Names: BACE1 (BACE, KIAA1149)
EC: 3.4.23.46
Find proteins for P56817 (Homo sapiens)
Go to Gene View: BACE1
Go to UniProtKB:  P56817
Entity ID: 2
MoleculeChainsSequence LengthOrganismDetails
BACE-1 EXOSITE PEPTIDE
B
13N/AMutation(s): 0 
Protein Feature View is not available: No corresponding UniProt sequence found.
Small Molecules
Ligands 1 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
BSD
Query on BSD

Download SDF File 
Download CCD File 
A
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[methyl(methylsulfonyl)amino]-N'-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide
C36 H42 N4 O6 S
HIQWWDCRULXYDF-SWROZOJRSA-N
 Ligand Interaction
Modified Residues  1 Unique
IDChainsTypeFormula2D DiagramParent
ACE
Query on ACE
B
NON-POLYMERC2 H4 O

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Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.49 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.175 
  • Space Group: P 32 2 1
Unit Cell:
Length (Å)Angle (°)
a = 101.493α = 90.00
b = 101.493β = 90.00
c = 117.184γ = 120.00
Software Package:
Software NamePurpose
PHASERphasing
XDSdata reduction
REFMACrefinement
Aimlessdata scaling

Structure Validation

View Full Validation Report or Ramachandran Plots



Entry History 

Deposition Data

Revision History 

  • Version 1.0: 2017-09-27
    Type: Initial release
  • Version 1.1: 2017-11-01
    Type: Database references