3TS4

Human MMP12 in complex with L-glutamate motif inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.59 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.180 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Simple pseudo-dipeptides with a P2' glutamate: a novel inhibitor family of matrix metalloproteases and other metzincins.

Devel, L.Beau, F.Amoura, M.Vera, L.Cassar-Lajeunesse, E.Garcia, S.Czarny, B.Stura, E.A.Dive, V.

(2012) J Biol Chem 287: 26647-26656

  • DOI: https://doi.org/10.1074/jbc.M112.380782
  • Primary Citation of Related Structures:  
    3TS4, 3TSK, 3TT4, 3TVC, 4EFS

  • PubMed Abstract: 

    A series of pseudo-peptides with general formula X-l-Glu-NH(2) (with X corresponding to an acyl moiety with a long aryl-alkyl side chain) have been synthesized, evaluated as inhibitors of matrix metalloproteases (MMPs), and found to display remarkable nanomolar affinity. The loss in potency associated with a substitution of the P(2)' l-glutamate by a l-glutamine corroborates the importance of a carboxylate at this position. The binding mode of some of these inhibitors was characterized in solution and by x-ray crystallography in complex with various MMPs. The x-ray crystal structures reveal an unusual binding mode with the glutamate side chain chelating the active site zinc ion. Competition experiments between these inhibitors and acetohydroxamic acid, a small zinc-binding molecule, are in accord with the crystallographic results. One of these pseudo-dipeptides displays potency and selectivity toward MMP-12 similar to the best MMP-12 inhibitors reported to date. This novel family of pseudo peptides opens new opportunities to develop potent and selective inhibitors for several metzincins.


  • Organizational Affiliation

    CEA (Commissariat à l'Energie Atomique), iBiTec-S, Service d'Ingénierie Moléculaire de Protéines (SIMOPRO), CE Saclay, 91191 Gif/Yvette, Cedex, France. laurent.devel@cea.fr


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Macrophage metalloelastase159Homo sapiensMutation(s): 1 
Gene Names: HMEMMP12
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 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
EEG
Query on EEG

Download Ideal Coordinates CCD File 
G [auth A]N-{3-[4-(4-phenylthiophen-2-yl)phenyl]propanoyl}-L-alpha-glutamyl-L-alpha-glutamyl-amide
C29 H31 N3 O7 S
MMIHYNVQXYWTFM-GOTSBHOMSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
I [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
IMD
Query on IMD

Download Ideal Coordinates CCD File 
H [auth A]IMIDAZOLE
C3 H5 N2
RAXXELZNTBOGNW-UHFFFAOYSA-O
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
EEG PDBBind:  3TS4 Ki: 1.9 (nM) from 1 assay(s)
BindingDB:  3TS4 Ki: min: 1.92, max: 144 (nM) from 2 assay(s)
Binding MOAD:  3TS4 Ki: 1.9 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.59 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.180 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 70.09α = 90
b = 63.65β = 90
c = 37.37γ = 90
Software Package:
Software NamePurpose
DNAdata collection
MOLREPphasing
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-06-20
    Type: Initial release
  • Version 1.1: 2012-10-17
    Changes: Database references
  • Version 1.2: 2012-12-12
    Changes: Other
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description