3LIL

Human MMP12 in complex with non-zinc chelating inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.190 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.155 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Insights from selective non-phosphinic inhibitors of MMP-12 tailored to fit with an S1' loop canonical conformation.

Devel, L.Garcia, S.Czarny, B.Beau, F.LaJeunesse, E.Vera, L.Georgiadis, D.Stura, E.Dive, V.

(2010) J Biol Chem 285: 35900-35909

  • DOI: https://doi.org/10.1074/jbc.M110.139634
  • Primary Citation of Related Structures:  
    3LIK, 3LIL, 3LIR, 3LJG

  • PubMed Abstract: 

    After the disappointment of clinical trials with early broad spectrum synthetic inhibitors of matrix metalloproteinases (MMPs), the field is now resurging with a new focus on the development of selective inhibitors that fully discriminate between different members of the MMP family with several therapeutic applications in perspective. Here, we report a novel class of highly selective MMP-12 inhibitors, without a phosphinic zinc-binding group, designed to plunge deeper into the S(1)' cavity of the enzyme. The best inhibitor from this series, identified through a systematic chemical exploration, displays nanomolar potency toward MMP-12 and selectivity factors that range between 2 and 4 orders of magnitude toward a large set of MMPs. Comparison of the high resolution x-ray structures of MMP-12 in free state or bound to this new MMP-12 selective inhibitor reveals that this compound fits deeply within the S(1)' specificity cavity, maximizing surface/volume ratios, without perturbing the S(1)' loop conformation. This is in contrast with highly selective MMP-13 inhibitors that were shown to select a particular S(1)' loop conformation. The search for such compounds that fit precisely to preponderant S(1)' loop conformation of a particular MMP may prove to be an alternative effective strategy for developing selective inhibitors of MMPs.


  • Organizational Affiliation

    Commissariat à l'Energie Atomique, Service d'Ingénierie Moléculaire de Protéines, CE-Saclay, 91191 Gif/Yvette Cedex, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Macrophage metalloelastase159Homo sapiensMutation(s): 1 
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
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
EEA
Query on EEA

Download Ideal Coordinates CCD File 
G [auth A]N-{3-[3-(3'-chlorobiphenyl-4-yl)isoxazol-5-yl]propanoyl}-L-alpha-glutamyl-L-alpha-glutamyl-amide
C28 H29 Cl N4 O8
KOVQMCGGWATESY-VXKWHMMOSA-N
HAE
Query on HAE

Download Ideal Coordinates CCD File 
H [auth A]ACETOHYDROXAMIC ACID
C2 H5 N O2
RRUDCFGSUDOHDG-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
EEA BindingDB:  3LIL Ki: 8.3 (nM) from 1 assay(s)
PDBBind:  3LIL Ki: 8.3 (nM) from 1 assay(s)
Binding MOAD:  3LIL Ki: 8.3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.190 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.155 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.782α = 90
b = 62.667β = 90
c = 37.648γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
REFMACrefinement
DNAdata collection
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-09-01
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2012-12-12
    Changes: Other
  • Version 1.3: 2019-07-17
    Changes: Data collection, Refinement description
  • Version 1.4: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description