6HV2

MMP-13 in complex with the peptide IMISF


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.71 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.214 
  • R-Value Observed: 0.216 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Drug Design Inspired by Nature: Crystallographic Detection of an Auto-Tailored Protease Inhibitor Template.

Gall, F.M.Hohl, D.Frasson, D.Wermelinger, T.Mittl, P.R.E.Sievers, M.Riedl, R.

(2019) Angew Chem Int Ed Engl 58: 4051-4055

  • DOI: https://doi.org/10.1002/anie.201812348
  • Primary Citation of Related Structures:  
    6HV2

  • PubMed Abstract: 

    De novo drug discovery is still a challenge in the search for potent and selective modulators of therapeutically relevant target proteins. Here, we disclose the unexpected discovery of a peptidic ligand 1 by X-ray crystallography, which was auto-tailored by the therapeutic target MMP-13 through partial self-degradation and subsequent structure-based optimization to a highly potent and selective β-sheet peptidomimetic inhibitor derived from the endogenous tissue inhibitors of metalloproteinases (TIMPs). The incorporation of non-proteinogenic amino acids in combination with a cyclization strategy proved to be key for the de novo design of TIMP peptidomimetics. The optimized cyclic peptide 4 (ZHAWOC7726) is membrane permeable with an IC 50 of 21 nm for MMP-13 and an attractive selectivity profile with respect to a polypharmacology approach including the anticancer targets MMP-2 (IC 50 : 170 nm) and MMP-9 (IC 50 : 140 nm).


  • Organizational Affiliation

    Institute of Chemistry and Biotechnology, Center of Organic and Medicinal Chemistry, ZHAW Zurich University of Applied Sciences, Einsiedlerstrasse 31, 8820, Wädenswil, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Collagenase 3168Homo 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

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Collagenase 35Homo 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  
UniProt GroupP45452
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.928α = 90
b = 68.928β = 90
c = 133.563γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-01-30
    Type: Initial release
  • Version 1.1: 2019-02-13
    Changes: Data collection, Database references
  • Version 1.2: 2019-03-20
    Changes: Data collection, Database references
  • Version 1.3: 2020-04-22
    Changes: Database references
  • Version 1.4: 2024-01-24
    Changes: Data collection, Database references, Derived calculations, Refinement description