3LIR

Human MMP12 in complex with non-zinc chelating inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.161 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


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
EEC
Query on EEC

Download Ideal Coordinates CCD File 
G [auth A]N-[3-(3-phenylisoxazol-5-yl)propanoyl]-L-alpha-glutamyl-L-alpha-glutamyl-amide
C22 H26 N4 O8
LIIRZRQVACDFBI-HOTGVXAUSA-N
GLY
Query on GLY

Download Ideal Coordinates CCD File 
H [auth A]GLYCINE
C2 H5 N O2
DHMQDGOQFOQNFH-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
EEC BindingDB:  3LIR Ki: 119 (nM) from 1 assay(s)
PDBBind:  3LIR Ki: 119 (nM) from 1 assay(s)
Binding MOAD:  3LIR Ki: 119 (nM) from 1 assay(s)
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.161 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.997α = 90
b = 63.171β = 90
c = 37.573γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
REFMACrefinement
DNAdata collection
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


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: Advisory, Data collection, Refinement description
  • Version 1.4: 2023-09-06
    Changes: Advisory, Data collection, Database references, Derived calculations, Refinement description