5UWK

Matrix metalloproteinase-13 complexed with selective inhibitor compound (S)-10a


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.148 
  • R-Value Observed: 0.150 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors.

Choi, J.Y.Fuerst, R.Knapinska, A.M.Taylor, A.B.Smith, L.Cao, X.Hart, P.J.Fields, G.B.Roush, W.R.

(2017) J Med Chem 60: 5816-5825

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b00514
  • Primary Citation of Related Structures:  
    5UWK, 5UWL, 5UWM, 5UWN

  • PubMed Abstract: 

    We describe the use of comparative structural analysis and structure-guided molecular design to develop potent and selective inhibitors (10d and (S)-17b) of matrix metalloproteinase 13 (MMP-13). We applied a three-step process, starting with a comparative analysis of the X-ray crystallographic structure of compound 5 in complex with MMP-13 with published structures of known MMP-13·inhibitor complexes followed by molecular design and synthesis of potent but nonselective zinc-chelating MMP inhibitors (e.g., 10a and 10b). After demonstrating that the pharmacophores of the chelating inhibitors (S)-10a, (R)-10a, and 10b were binding within the MMP-13 active site, the Zn 2+ chelating unit was replaced with nonchelating polar residues that bridged over the Zn 2+ binding site and reached into a solvent accessible area. After two rounds of structural optimization, these design approaches led to small molecule MMP-13 inhibitors 10d and (S)-17b, which bind within the substrate-binding site of MMP-13 and surround the catalytically active Zn 2+ ion without chelating to the metal. These compounds exhibit at least 500-fold selectivity versus other MMPs.


  • Organizational Affiliation

    Department of Chemistry, Scripps Florida , 130 Scripps Way, Jupiter, Florida 33458, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Collagenase 3
A, B
172Homo sapiensMutation(s): 0 
Gene Names: MMP13
EC: 3.4.24
UniProt & NIH Common Fund Data Resources
Find proteins for P45452 (Homo sapiens)
Explore P45452 
Go to UniProtKB:  P45452
PHAROS:  P45452
GTEx:  ENSG00000137745 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP45452
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
8OM
Query on 8OM

Download Ideal Coordinates CCD File 
H [auth A],
N [auth B]
(S)-3-methyl-2-(4'-(((4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl)thio)methyl)-[1,1'-biphenyl]-4-ylsulfonamido)butanoic acid
C25 H27 N3 O5 S2
GPMDDUDPGNYEJM-QFIPXVFZSA-N
ZN
Query on ZN

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

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
K [auth B]
L [auth B]
E [auth A],
F [auth A],
G [auth A],
K [auth B],
L [auth B],
M [auth B]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
8OM Binding MOAD:  5UWK Ki: 2.3 (nM) from 1 assay(s)
BindingDB:  5UWK Ki: 2.3 (nM) from 1 assay(s)
IC50: 2.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.148 
  • R-Value Observed: 0.150 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.784α = 90
b = 57.155β = 90
c = 120.564γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-07-12
    Type: Initial release
  • Version 1.1: 2017-07-26
    Changes: Database references
  • Version 1.2: 2023-10-04
    Changes: Data collection, Database references, Derived calculations, Refinement description