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 (2002)
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN 16(3): 213-225.

Zeitschriftenaufsatz | Veröffentlicht | Englisch
 
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Autor*in
Aschi, M; Roccatano, D; Di Nola, A; Gallina, C; Gavuzzo, E; Pochetti, G; Pieper, M; Tschesche, HaraldUniBi; Mazza, F
Abstract / Bemerkung
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.
Stichworte
enzyme-inhibitor binding; human neutrophil; collagenase; molecular dynamics; essential dynamics
Erscheinungsjahr
2002
Zeitschriftentitel
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
Band
16
Ausgabe
3
Seite(n)
213-225
ISSN
0920-654X
Page URI
https://pub.uni-bielefeld.de/record/1613692

Zitieren

Aschi M, Roccatano D, Di Nola A, et al. 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. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN. 2002;16(3):213-225.
Aschi, M., Roccatano, D., Di Nola, A., Gallina, C., Gavuzzo, E., Pochetti, G., Pieper, M., et al. (2002). 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. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 16(3), 213-225. doi:10.1023/A:1020178822319
Aschi, M., Roccatano, D., Di Nola, A., Gallina, C., Gavuzzo, E., Pochetti, G., Pieper, M., Tschesche, H., and Mazza, F. (2002). 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. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN 16, 213-225.
Aschi, M., et al., 2002. 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. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 16(3), p 213-225.
M. Aschi, et al., “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”, JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, vol. 16, 2002, pp. 213-225.
Aschi, M., Roccatano, D., Di Nola, A., Gallina, C., Gavuzzo, E., Pochetti, G., Pieper, M., Tschesche, H., Mazza, F.: 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. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN. 16, 213-225 (2002).
Aschi, M, Roccatano, D, Di Nola, A, Gallina, C, Gavuzzo, E, Pochetti, G, Pieper, M, Tschesche, Harald, and Mazza, F. “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”. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN 16.3 (2002): 213-225.

7 Zitationen in Europe PMC

Daten bereitgestellt von Europe PubMed Central.

Modelling the restoration of wild-type dynamic behaviour in DeltaF508-CFTR NBD1 by 8-cyclopentyl-1,3-dipropylxanthine.
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Coiro VM, Di Nola A, Vanoni MA, Vanoni MA, Aschi M, Coda A, Curti B, Roccatano D., Protein Sci 13(11), 2004
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