5M5Q

COPS5(2-257) IN COMPLEX WITH A AZAINDOLE (COMPOUND 4)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.198 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Azaindoles as Zinc-Binding Small-Molecule Inhibitors of the JAMM Protease CSN5.

Altmann, E.Erbel, P.Renatus, M.Schaefer, M.Schlierf, A.Druet, A.Kieffer, L.Sorge, M.Pfister, K.Hassiepen, U.Jones, M.Ruedisser, S.Ostermeier, D.Martoglio, B.Jefferson, A.B.Quancard, J.

(2017) Angew Chem Int Ed Engl 56: 1294-1297

  • DOI: https://doi.org/10.1002/anie.201608672
  • Primary Citation of Related Structures:  
    5M5Q

  • PubMed Abstract: 

    CSN5 is the zinc metalloprotease subunit of the COP9 signalosome (CSN), which is an important regulator of cullin-RING E3 ubiquitin ligases (CRLs). CSN5 is responsible for the cleavage of NEDD8 from CRLs, and blocking deconjugation of NEDD8 traps the CRLs in a hyperactive state, thereby leading to auto-ubiquitination and ultimately degradation of the substrate recognition subunits. Herein, we describe the discovery of azaindoles as a new class of CSN5 inhibitors, which interact with the active-site zinc ion of CSN5 through an unprecedented binding mode. The best compounds inhibited CSN5 with nanomolar potency, led to degradation of the substrate recognition subunit Skp2 in cells, and reduced the viability of HCT116 cells.


  • Organizational Affiliation

    Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
COP9 signalosome complex subunit 5257Homo sapiensMutation(s): 0 
Gene Names: COPS5CSN5JAB1
EC: 3.4
UniProt & NIH Common Fund Data Resources
Find proteins for Q92905 (Homo sapiens)
Explore Q92905 
Go to UniProtKB:  Q92905
PHAROS:  Q92905
GTEx:  ENSG00000121022 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ92905
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7K1
Query on 7K1

Download Ideal Coordinates CCD File 
C [auth A]1-[(3~{R})-3-(1~{H}-benzimidazol-2-yl)morpholin-4-yl]-3-[2-(4-methyl-2-phenyl-phenyl)-1~{H}-pyrrolo[2,3-b]pyridin-3-yl]propan-1-one
C34 H31 N5 O2
NWWYHKMOCXEJLJ-PMERELPUSA-N
MPD
Query on MPD

Download Ideal Coordinates CCD File 
D [auth A](4S)-2-METHYL-2,4-PENTANEDIOL
C6 H14 O2
SVTBMSDMJJWYQN-YFKPBYRVSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
7K1 Binding MOAD:  5M5Q IC50: 90 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.198 
  • Space Group: I 4
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 102.365α = 90
b = 102.365β = 90
c = 69.048γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-01-11
    Type: Initial release
  • Version 1.1: 2017-01-25
    Changes: Database references