1I73

COMPLEX OF PRO-LEU-L-TRP PHOSPHONATE WITH THE CATALITIC DOMAIN OF MATRIX METALLO PROTEINASE-8 (MET80 FORM)

Summary for 1I73

• Entry DOI: 10.2210/pdb1i73/pdb
• Related: 1BZS 1I76 1JAP
• Descriptor: NEUTROPHIL COLLAGENASE, THREE RESIDUE PEPTIDE INHIBITOR, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: metalloprotease-inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasmic granule: P22894
• Total number of polymer chains: 2
• Total formula weight: 18817.20

Authors

Gavuzzo, E.,Pochetti, G.,Mazza, F.,Gallina, C.,Gorini, B.,D'Alessio, S.,Pieper, M.,Tschesche, H.,Tucker, P.A. (deposition date: 2001-03-07, release date: 2001-03-21, Last modification date: 2023-08-09)

Primary citation

Gavuzzo, E.,Pochetti, G.,Mazza, F.,Gallina, C.,Gorini, B.,D'Alessio, S.,Pieper, M.,Tschesche, H.,Tucker, P.A.
Two crystal structures of human neutrophil collagenase, one complexed with a primed- and the other with an unprimed-side inhibitor: implications for drug design.
J.Med.Chem., 43:3377-3385, 2000

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.

PubMed: 10978185
DOI: 10.1021/jm9909589

Experimental method

X-RAY DIFFRACTION (1.4 Å)