5CZM

Crystal structure of a mutated catalytic domain of Human MMP12 in complex with RXP470


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 Å
  • R-Value Free: 0.174 
  • R-Value Work: 0.145 
  • R-Value Observed: 0.147 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Zinc-Metalloproteinase Inhibitors: Evaluation of the Complex Role Played by the Zinc-Binding Group on Potency and Selectivity.

Rouanet-Mehouas, C.Czarny, B.Beau, F.Cassar-Lajeunesse, E.Stura, E.A.Dive, V.Devel, L.

(2017) J Med Chem 60: 403-414

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b01420
  • Primary Citation of Related Structures:  
    5CXA, 5CZM, 5D2B, 5D3C

  • PubMed Abstract: 

    The most exploited strategy to develop potent zinc-metalloprotease inhibitors relies on a core zinc chelator and a peptidic or nonpeptidic scaffold that provides supplementary interactions for optimized potency and selectivity. Applied to matrix metalloproteases (MMPs) with highly conserved catalytic domains, this strategy failed to identify inhibitors with the desired selectivity profiles. To question the precise role of the zinc-binding group (ZBG), we have carried out a study on MMP-12 inhibitors with a common peptidic core but different ZBGs. We find that exchanging the ZBG modifies inhibitor positioning and affects its dynamics and selectivity. The binding properties of these compounds were compared through biochemical, structural, and calorimetric studies, showing a complex interplay between cooperative interactions and dynamics dictated by the ZBG. Improving selectivity will require expanding the ZBG repertoire within inhibitor libraries, since relying on a single ZBG significantly decreases our chance to identify effective inhibitors.


  • Organizational Affiliation

    Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), IBITECS, CEA, Université Paris-Saclay , Gif/Yvette F-91191, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Macrophage metalloelastase159Homo sapiensMutation(s): 2 
Gene Names: MMP12HME
EC: 3.4.24.65
UniProt & NIH Common Fund Data Resources
Find proteins for P39900 (Homo sapiens)
Explore P39900 
Go to UniProtKB:  P39900
PHAROS:  P39900
GTEx:  ENSG00000262406 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP39900
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
R47 BindingDB:  5CZM Ki: min: 0.19, max: 0.26 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 Å
  • R-Value Free: 0.174 
  • R-Value Work: 0.145 
  • R-Value Observed: 0.147 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.97α = 90
b = 63.29β = 90
c = 35.91γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
MxCuBEdata collection
XDSdata reduction
MOLREPphasing
Cootmodel building
XDSdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-08-10
    Type: Initial release
  • Version 1.1: 2016-12-21
    Changes: Database references, Non-polymer description
  • Version 1.2: 2017-01-11
    Changes: Database references
  • Version 1.3: 2017-01-25
    Changes: Database references
  • Version 1.4: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description