1I76

COMPLEX OF 2-(BIPHENYL-4-SULFONYL)-1,2,3,4-TETRAHYDRO-ISOQUINOLINE-3-CARBOXYLIC ACID (D-TIC DERIVATIVE) WITH T CATALITIC DOMAIN OF MATRIX METALLO PROTEINASE-8 (MET80 FORM)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.171 
  • R-Value Work: 0.129 
  • R-Value Observed: 0.132 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Two crystal structures of human neutrophil collagenase, one complexed with a primed- and the other with an unprimed-side inhibitor: implications for drug design.

Gavuzzo, E.Pochetti, G.Mazza, F.Gallina, C.Gorini, B.D'Alessio, S.Pieper, M.Tschesche, H.Tucker, P.A.

(2000) J Med Chem 43: 3377-3385

  • DOI: https://doi.org/10.1021/jm9909589
  • Primary Citation of Related Structures:  
    1I73, 1I76

  • PubMed Abstract: 

    Two crystal structures of human neutrophil collagenase (HNC, MMP-8), one complexed with a primed- and the other with an unprimed-side inhibitor, were determined using synchrotron radiation at 100 K. Both inhibitors contain non-hydroxamate zinc-binding functions. The Pro-Leu-L-Trp(P)(OH)(2) occupies the unprimed region of the active site, furnishes new structural information regarding interaction between the catalytic zinc ion and the phosphonate group, and is the only example of occupation of the S(1) subsite of MMP-8 by the bulky tryptophan side chain. The (R)-2-(biphenyl-4-ylsulfonyl)-1,2,3, 4-tetrahydroisochinolin-3-carboxylic acid, a conformationally constrained D-Tic derivative, accommodates its biphenyl substituent into the deep primary specificity S(1)' subsite, inducing a widening of the entrance to this pocket; this modification of the protein, mainly consisting in a shift of the segment centered at Pro217, is observed for the first time in MMP-8 complexes. Cation-aromatic interactions can stabilize the formation of both complexes, and the beneficial effect of aromatic substituents in proximity of the catalytic zinc ion is discussed. The phosphonate group bound to either a primed- or unprimed-side inhibitor maintains the same relative position with respect to the catalytic zinc ion, suggesting that this binding function can be exploited for the design of combined inhibitors assembled to interact with both primed and unprimed regions of the active cleft.


  • Organizational Affiliation

    Istituto di Strutturistica Chimica, CNR, C. P. n. 10, 00016 Monterotondo Stazione, Roma, Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
NEUTROPHIL COLLAGENASE163Homo 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
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.171 
  • R-Value Work: 0.129 
  • R-Value Observed: 0.132 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 32.99α = 90
b = 68.684β = 90
c = 70.584γ = 90
Software Package:
Software NamePurpose
X-PLORmodel building
SHELXLrefinement
DENZOdata reduction
SCALEPACKdata scaling
X-PLORphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2001-03-21
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-04
    Changes: Refinement description
  • Version 1.4: 2018-01-24
    Changes: Database references
  • Version 1.5: 2023-08-09
    Changes: Data collection, Database references, Derived calculations, Refinement description