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Crystallographic analysis of transition state mimics bound to penicillopepsin: difluorostatine- and difluorostatone-containing peptides.

James MN, Sielecki AR, Hayakawa K, Gelb MH
Biochemistry 31 3872-86 (1992)
Cited: 42 times
EuropePMC logo PMID: 1567842

Abstract

Difluorostatine- and difluorostatone-containing peptides have been evaluated as potent inhibitors of penicillopepsin, a member of the aspartic proteinase family of enzymes. Isovaleryl-Val-Val-StaF2NHCH3 [StaF2 = (S)-4-amino-2,2-difluoro-(R)-3-hydroxy-6-methylheptanoic acid] and isovaleryl-Val-Val-StoF2NHCH3 [StoF2 = (S)-4-amino-2,2-difluoro-3-oxo-6-methylheptanoic acid] have measured Ki's of 10 x 10(-9) and 1 x 10(-9) M, respectively, with this fungal proteinase. The StoF2-containing peptide binds 32-fold more tightly to the enzyme than the analogous peptide containing the non-fluorinated statine ethyl ester. Each compound was cocrystallized with penicillopepsin, intensity data were collected to 1.8-A resolution, and the atomic coordinates were refined to an R factor [formula: see text] of 0.131 for both complexes. The inhibitors bind in the active site of penicillopepsin in much the same fashion as do other statine-containing inhibitors of penicillopepsin analyzed earlier [James, M. N. G., Sielecki, A. Salituro, F., Rich, D. H., & Hofmann, T. (1982) Proc. Natl. Acad. Sci. U.S.A. 79, 6137-6141; James, M.N.G., Sielecki, A., & Hofmann, T. (1985) in Aspartic Proteinases and their Inhibitors (Kosta, V., Ed.) pp 163-177, Walter deGruyter, Berlin]. The (R)-3-hydroxyl group in StaF2 binds between the active site carboxyl groups of Asp33 and Asp213, making hydrogen-bonding contacts to each one. The ketone functional group of the StoF2 inhibitor is bound as a hydrated species, with the gem-diol situated between the two aspartic acid carboxyl groups in a manner similar to that predicted for the tetrahedral intermediate expected during the catalytic hydrolysis of a peptide bond [James, M. N. G., & Sielecki, A. (1985) Biochemistry 24, 3701-3713]. One hydrogen-bonding interaction from the "outer" hydroxyl group is made to O delta 1 of Asp33, and the "inner" hydroxyl group forms two hydrogen-bonding contacts, one to each of the carboxyl groups of Asp33 (O delta 2) and Asp213 (O delta 2). The only structural difference between the StaF2 and StoF2 inhibitors that accounts for the factor of 10 in their Ki's is the additional (R)-3-OH group on the tetrahedral sp3 carbon atom of the hydrated StoF2 inhibitor. The intermolecular interactions involving the fluorine atoms of each inhibitor are normal van der Waals contacts to one of the carboxyl oxygen atoms of Asp213 (F2-O delta 2 Asp213, 2.9 A). The observed stereochemistry of the bound StoF2 group in the active site of penicillopepsin has stimulated our reappraisal of the catalytic pathway for the aspartic proteinases.(ABSTRACT TRUNCATED AT 400 WORDS)

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Related citations provided by authors (7)

  1. Aspartic Proteinases and Their Catalytic Pathway. James MNG, Sielecki AR Biological Macromolecules and Assemblies 3 414- (1987)
  2. Stereochemical analysis of peptide bond hydrolysis catalyzed by the aspartic proteinase penicillopepsin.. James MN, Sielecki AR Biochemistry 24 3701-13 (1985)
  3. X-Ray Diffraction Studies on Penicillopepsin and its Complexes: The Hydrolytic Mechanism. James MNG, Sielecki AR, Hofmann T Aspartic Proteinases and Their Inhibitors 163- (1985)
  4. Effect of Ph on the Activities of Penicillopepsin and Rhizopus Pepsin and a Proposal for the Productive Substrate Binding Mode in Penicillopepsin. Hofmann T, Hodges RS, James MNG Biochemistry 23 635- (1984)
  5. Crystallographic Analysis of a Pepstatin Analogue Binding to the Aspartyl Proteinase Penicillopepsin at 1.8 Angstroms Resolution. James MNG, Sielecki AR, Moult J Peptides: Structure and Function, Proceedings of the of the Eighth American Peptide Symposium 521- (1983)
  6. Structure and Refinement of Penicillopepsin at 1.8 Angstroms Resolution. James MNG, Sielecki AR J. Mol. Biol. 163 299- (1983)
  7. Conformational flexibility in the active sites of aspartyl proteinases revealed by a pepstatin fragment binding to penicillopepsin.. James MN, Sielecki A, Salituro F, Rich DH, Hofmann T Proc Natl Acad Sci U S A 79 6137-41 (1982)

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