1A86

MMP8 WITH MALONIC AND ASPARTIC ACID BASED INHIBITOR


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Structure of malonic acid-based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data.

Brandstetter, H.Engh, R.A.Von Roedern, E.G.Moroder, L.Huber, R.Bode, W.Grams, F.

(1998) Protein Sci 7: 1303-1309

  • DOI: https://doi.org/10.1002/pro.5560070605
  • Primary Citation of Related Structures:  
    1A85, 1A86

  • PubMed Abstract: 

    Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases, which have been implicated in various disease processes. Various classes of MMP inhibitors, including hydroxamic acids, phosphinic acids, and thiols, have been previously described. Most of these mimic peptides, and most likely bind analogous to the corresponding peptide substrates. Among the hydroxamic acids, malonic acid derivatives have been used as MMP inhibitors, although optimization of their inhibition potency was not successful. Here we report the design of malonic acid-based inhibitors using the X-ray structure of a collagenase/inhibitor complex, which revealed a nonsubstrate-like binding mode. The proposed beta-type turn-like conformation for the improved inhibitors was confirmed by X-ray crystallography. The observation of nonsubstrate-like binding confirms the original strategy for structure-based modeling of improved malonic acid inhibitors, and explains kinetic data that are inconsistent with substrate-like binding. Detailed interactions for the improved inhibitors seen in the crystal structure also suggest possibilities for further modifications in cycles of structure based drug design. Indeed, we have designed nonpeptidic inhibitors with approximately 500-fold improved inhibition based on these structures.


  • Organizational Affiliation

    Max-Planck-Institut für Biochemie, Abteilung Strukturforschung, Martinsried, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
MMP-8158Homo sapiensMutation(s): 0 
EC: 3.4.24.34
UniProt & NIH Common Fund Data Resources
Find proteins for P22894 (Homo sapiens)
Explore P22894 
Go to UniProtKB:  P22894
PHAROS:  P22894
GTEx:  ENSG00000118113 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP22894
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0ZB
Query on 0ZB

Download Ideal Coordinates CCD File 
B [auth A]N-benzyl-N~2~-[(2R)-2-(hydroxycarbamoyl)-4-methylpentanoyl]-L-alpha-asparagine
C18 H25 N3 O6
JXOYCIWPPBHZCO-KBPBESRZSA-N
ZN
Query on ZN

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

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Biologically Interesting Molecules (External Reference) 1 Unique
Entity ID: 2
IDChains NameType/Class2D Diagram3D Interactions
PRD_000371 (0ZB)
Query on PRD_000371
B [auth A]HONH-iBM-L-Asp-NHBnPeptide-like / Inhibitor
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 33.14α = 90
b = 69.43β = 90
c = 72.62γ = 90
Software Package:
Software NamePurpose
X-PLORrefinement

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 1999-05-04
    Type: Initial release
  • Version 1.1: 2008-03-24
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary, Version format compliance
  • Version 1.3: 2012-12-12
    Changes: Other
  • Version 1.4: 2024-02-07
    Changes: Data collection, Database references, Derived calculations, Other