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Crystal structures of alpha-mercaptoacyldipeptides in the thermolysin active site: structural parameters for a Zn monodentation or bidentation in metalloendopeptidases.

Gaucher JF, Selkti M, Tiraboschi G, Prangé T, Roques BP, Tomas A, Fournié-Zaluski MC
Biochemistry 38 12569-76 (1999)
Related entries: 1lna, 1lnb, 1lnc, 1lnd, 1lne, 1lnf, 1qf1, 1qf2

Cited: 28 times
EuropePMC logo PMID: 10504225

Abstract

Three alpha-mercaptoacyldipeptides differing essentially in the size of their C-terminal residues have been crystallized in the thermolysin active site. A new mode of binding was observed for 3 [HS-CH(CH(2)Ph)CO-Phe-Tyr] and 4 [HS-CH((CH(2))(4)CH(3))CO-Phe-Ala], in which the mercaptoacyl moieties act as bidentates with Zn-S and Zn-O distances of 2.3 and 2.4 A, respectively, the side chains fitting the S(1), S(1)', and S(2)' pockets. Moreover, a distance of 3.1 A between the sulfur atom and the OE1 of Glu(143) suggests that they are H-bonded and that one of these atoms is protonated. This H-bond network involving Glu(143), the mercaptoacyl group of the inhibitor, and the Zn ion could be considered a "modified" transition state mimic of the peptide bond hydrolysis. Due to the presence of the hindering (5-phenyl)proline, the inhibitor HS-CH(CH(2)Ph)CO-Gly-(5-Ph)Pro (2) interacts through the usual Zn monodentation via the thiol group and occupancy of S(1)' and S(2)' subsites by the aromatic moieties, the proline ring being outside the active site. The inhibitory potencies are consistent with these structural data, with higher affinities for 3 (4.2 x 10(-)(8) M) and 4 (4.8 x 10(-)(8) M) than for 2 (1.2 x 10(-)(6) M). The extension of the results, obtained with thermolysin being considered as the model of physiological zinc metallopeptidases, allows inhibitor-recognition modes for other peptidases, such as angiotensin converting enzyme and neutral endopeptidase, to be proposed and opens interesting possibilities for the design of new classes of inhibitors.

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  16. Homology modeling of hemagglutinin/protease [HA/P (vibriolysin)] from Vibrio cholerae: sequence comparision, residue interactions and molecular mechanism. Lutfullah G, Amin F, Khan Z, Azhar N, Azim MK, Noor S, Shoukat K. Protein J 27 105-114 (2008)
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  23. The Drosophila melanogaster Neprilysin Nepl15 is involved in lipid and carbohydrate storage. Banerjee S, Woods C, Burnett M, Park SJ, Ja WW, Curtiss J. Sci Rep 11 2099 (2021)


Related citations provided by authors (4)

  1. Design of orally active dual inhibitors of neutral endopeptidase and angiotensin-converting enzyme with long duration of action.. Fournie-Zaluski MC, Coric P, Thery V, Gonzalez W, Meudal H, Turcaud S, Michel JB, Roques BP J Med Chem 39 2594-608 (1996)
  2. Optimal recognition of neutral endopeptidase and angiotensin-converting enzyme active sites by mercaptoacyldipeptides as a means to design potent dual inhibitors.. Coric P, Turcaud S, Meudal H, Roques BP, Fournie-Zaluski MC J Med Chem 39 1210-9 (1996)
  3. Structural analysis of zinc substitutions in the active site of thermolysin.. Holland DR, Hausrath AC, Juers D, Matthews BW Protein Sci 4 1955-65 (1995)
  4. Three-dimensional structure of thermolysin.. Matthews BW, Jansonius JN, Colman PM, Schoenborn BP, Dupourque D Nat New Biol 238 37-41 (1972)

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