Computational study of the catalytic domain of human neutrophil collagenase. Specific role of the S-3 and S '(3) subsites in the interaction with a phosphonate inhibitor
Aschi M, Roccatano D, Di Nola A, Gallina C, Gavuzzo E, Pochetti G, Pieper M, Tschesche H, Mazza F
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
16 (3): 213-225 MAR 2002

FULL TEXT

Abstract:

Human neutrophil collagenase (HNC, MMP-8) is one of the target enzymes for drug treatment of pathologic extracellular matrix degradation. Peptidomimetic inhibitors bind in the S'-side of the enzyme active site occupying the S-1(') primary specificity pocket by their large hydrophobic side-chains. The crystal structure of the complex between the catalytic domain of MMP-8 and Pro-Leu-l-Trp(P)(OH)(2) (PLTP) showed that this phosphonate inhibitor binds in the S side of the active site. This finding was unexpected since it represents the first example of accommodation of the bulky Trp indolyl chain in the S-1 rather than in the S-1(') subsite. Dynamical and structural factors favouring this uncommon mode of binding were therefore investigated. MD simulations performed on the uncomplexed enzyme show that its structure in aqueous solution is only slightly different from the crystal structure found in the complex with PLTP. ED analysis of the MD simulations, performed on PLTP alternatively interacting with the S- or S'-side of the active site, shows that the enzyme fluctuation increases in both cases. The main contribution to the overall enzyme fluctuation is given by the loop 164-173. The fluctuation of this loop is spread over more degrees of freedom when PLTP interacts with the S-side. This dynamical factor can enhance the preference of PLTP for the S subsites of MMP-8. MD simulations also show that ligation of PLTP in the S subsites is further favoured by better zinc chelation, a cation-pi interaction at the S-3 subsite and unstrained binding conformations. The role of the S-3, S-3(') and S-1(') subsites in determining the inhibitor binding is discussed.

Author Keywords:

enzyme-inhibitor binding, essential dynamics, human neutrophil collagenase, molecular dynamics

KeyWords Plus:

RAY CRYSTAL-STRUCTURE, CIS PEPTIDE-BONDS, ADAMALYSIN-II, SNAKE-VENOM, MATRIX METALLOPROTEINASES, MOLECULAR-DYNAMICS, SIDE INHIBITOR, BINDING MODE, DRUG DESIGN, HYDROXAMATE

Addresses:

Mazza F, Univ Aquila, Dipartimento Chim Ingn Chim & Mat, V Vetoio, I-67010 Coppito, Italy
Univ Aquila, Dipartimento Chim Ingn Chim & Mat, I-67010 Coppito, Italy
Univ Roma La Sapienza, Dipartimento Chim, I-00185 Rome, Italy
Univ G DAnnunzio, Dipartimento Sci Farmaco, I-66100 Chieti, Italy
CNR, Ist Strutturist Chim, I-00016 Monterotondo, Rome, Italy
Univ Bielefeld, Fak Chem, Abt Biochem 1, D-33615 Bielefeld, Germany