Two Crystal Structures of Human Neutrophil Collagenase, One Complexed with a Primed- and the Other with an Unprimed-Side Inhibitor:  Implications for Drug Design

• Published in: Journal of medicinal chemistry Vol. 43; no. 18; pp. 3377 - 3385
• Main Authors: Gavuzzo, Enrico, Pochetti, Giorgio, Mazza, Fernando, Gallina, Carlo, Gorini, Barbara, D'Alessio, Silvana, Pieper, Michael, Tschesche, Harald, Tucker, Paul A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 07.09.2000; Amer Chemical Soc
• Subjects: Catalytic Domain; Chemistry, Medicinal; Crystallography, X-Ray; Drug Design; Humans; Isoquinolines - chemistry; Life Sciences & Biomedicine; Ligands; Matrix Metalloproteinase 8 - chemistry; Matrix Metalloproteinase Inhibitors; Models, Molecular; Molecular Conformation; Oligopeptides - chemistry; Organophosphonates - chemistry; Pharmacology & Pharmacy; Protease Inhibitors - chemistry; Protein Binding; Science & Technology; Sulfones - chemistry; Tetrahydroisoquinolines; SUBSTRATE-SPECIFICITY; MOLECULAR RECOGNITION; CATALYTIC DOMAIN; ADAMALYSIN-II; SEQUENCE SPECIFICITIES; X-RAY STRUCTURE; IV COLLAGENASES; POTENT INHIBITORS; MATRIX METALLOPROTEINASE INHIBITORS; SULFONAMIDE JUNCTION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9909589

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-TrpP(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 S1 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 S1‘ 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.