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Structural study of the complex between human pepsin and a phosphorus-containing peptidic -transition-state analog.

Fujinaga M, Cherney MM, Tarasova NI, Bartlett PA, Hanson JE, James MN
Acta Crystallogr D Biol Crystallogr 56 272-9 (2000)
Cited: 12 times
EuropePMC logo PMID: 10713513

Abstract

The refined crystal structure of the complex between human pepsin and a synthetic phosphonate inhibitor, Iva-Val-Val-Leu(P)-(O)Phe-Ala-Ala-OMe [Iva = isovaleryl, Leu(P) = the phosphinic acid analog of L-leucine, (O)Phe = L-3-phenyllactic acid, OMe = methyl ester], is presented. The structure was refined using diffraction data between 30 and 1.96 A resolution to a final R factor ( summation operator| |F(o)| - |F(c)| | / summation operator|F(o)|, where |F(o)| and |F(c)| are the observed and calculated structure-factor amplitudes, respectively) of 20.0%. The interactions of the inhibitor with the enzyme show the locations of the binding sites on the enzyme from S4 to S3'. Modeling of the inhibitor binding to porcine pepsin shows very similar binding sites, except at S4. Comparison of the complex structure with the structures of related inhibitors bound to penicillopepsin helps to rationalize the observed differences in the binding constants. The convergence of reaction mechanisms and geometries in different families of proteinases is also discussed.

Reviews - 1qrp mentioned but not cited (2)

  1. Mechanisms of Proteolytic Enzymes and Their Inhibition in QM/MM Studies. Elsässer B, Goettig P. Int J Mol Sci 22 3232 (2021)
  2. Pepsin-like aspartic proteases (PAPs) as model systems for combining biomolecular simulation with biophysical experiments. Bhakat S. RSC Adv 11 11026-11047 (2021)

Articles - 1qrp mentioned but not cited (4)

  1. Comparative void-volume analysis of psychrophilic and mesophilic enzymes: Structural bioinformatics of psychrophilic enzymes reveals sources of core flexibility. Paredes DI, Watters K, Pitman DJ, Bystroff C, Dordick JS. BMC Struct Biol 11 42 (2011)
  2. Purification and characterization of pepsins A1 and A2 from the Antarctic rock cod Trematomus bernacchii. Brier S, Maria G, Carginale V, Capasso A, Wu Y, Taylor RM, Borotto NB, Capasso C, Engen JR. FEBS J. 274 6152-6166 (2007)
  3. Statistical coupling analysis of aspartic proteinases based on crystal structures of the Trichoderma reesei enzyme and its complex with pepstatin A. Nascimento AS, Krauchenco S, Golubev AM, Gustchina A, Wlodawer A, Polikarpov I. J. Mol. Biol. 382 763-778 (2008)
  4. Discovery of new Schistosoma mansoni aspartyl protease inhibitors by structure-based virtual screening. Gomes BF, Senger MR, Moreira-Filho JT, Vasconcellos Junior FJ, Dantas RF, Owens R, Andrade CH, Neves BJ, Silva-Junior FP. Mem Inst Oswaldo Cruz 118 e230031 (2023)


Articles citing this publication (6)

  1. Analysis of crystal structures of aspartic proteinases: on the role of amino acid residues adjacent to the catalytic site of pepsin-like enzymes. Andreeva NS, Rumsh LD. Protein Sci. 10 2439-2450 (2001)
  2. Five atomic resolution structures of endothiapepsin inhibitor complexes: implications for the aspartic proteinase mechanism. Coates L, Erskine PT, Crump MP, Wood SP, Cooper JB. J. Mol. Biol. 318 1405-1415 (2002)
  3. Exploring the subsite specificity of Schistosoma mansoni aspartyl hemoglobinase through comparative molecular modelling. Silva FP, Ribeiro F, Katz N, Giovanni-De-Simone S. FEBS Lett. 514 141-148 (2002)
  4. Design, synthesis, and metal binding of novel Pseudo- oligopeptides containing two phosphinic acid groups. Ye Y, Liu M, Kao JL, Marshall GR. Biopolymers 89 72-85 (2008)
  5. Combining Molecular Dynamic Information and an Aspherical-Atom Data Bank in the Evaluation of the Electrostatic Interaction Energy in Multimeric Protein-Ligand Complex: A Case Study for HIV-1 Protease. Kumar P, Dominiak PM. Molecules 26 3872 (2021)
  6. The Intrinsic Pepsin Resistance of Interleukin-8 Can Be Explained from a Combined Bioinformatical and Experimental Approach. Anders G, Hassiepen U, Theisgen S, Heymann S, Muller L, Panigada T, Huster D, Samsonov SA. IEEE/ACM Trans Comput Biol Bioinform 15 300-308 (2018)


Related citations provided by authors (1)

  1. Crystal structure of human pepsin and its complex with pepstatin. Fujinaga M, Chernaia MM, Tarasova NI, Mosimann SC, James MNG Protein Sci. 4 960-972 (1995)

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