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The crystal structure of alpha-thrombin-hirunorm IV complex reveals a novel specificity site recognition mode.

Lombardi A, De Simone G, Nastri F, Galdiero S, Della Morte R, Staiano N, Pedone C, Bolognesi M, Pavone V
Protein Sci 8 91-5 (1999)
Cited: 8 times
EuropePMC logo PMID: 10210187

Abstract

The X-ray crystal structure of the human alpha-thrombin-hirunorm IV complex has been determined at 2.5 A resolution, and refined to an R-factor of 0.173. The structure reveals an inhibitor binding mode distinctive of a true hirudin mimetic, which justifies the high inhibitory potency and the selectivity of hirunorm IV. This novel inhibitor, composed of 26 amino acids, interacts through the N-terminal end with the alpha-thrombin active site in a nonsubstrate mode, and binds specifically to the fibrinogen recognition exosite through the C-terminal end. The backbone of the N-terminal tripeptide Chg1"-Arg2"-2Na13" (Chg, cyclohexyl-glycine; 2Na1, beta-(2-naphthyl)-alanine) forms a parallel beta-strand to the thrombin main-chain segment Ser214-Gly216. The Chg1" side chain occupies the S2 site, Arg2" penetrates into the S1 specificity site, while the 2Na13" side chain occupies the aryl binding site. The Arg2" side chain enters the S1 specificity pocket from a position quite apart from the canonical P1 site. This notwithstanding, the Arg2" side chain establishes the typical ion pair with the carboxylate group of Asp189.

Reviews - 4thn mentioned but not cited (1)

  1. Exosite Binding in Thrombin: A Global Structural/Dynamic Overview of Complexes with Aptamers and Other Ligands. Troisi R, Balasco N, Autiero I, Vitagliano L, Sica F. Int J Mol Sci 22 10803 (2021)

Articles - 4thn mentioned but not cited (2)

  1. Using reverse docking to identify potential targets for ginsenosides. Park K, Cho AE. J Ginseng Res 41 534-539 (2017)
  2. Assignment of a dubious gene cluster to melanin biosynthesis in the tomato fungal pathogen Cladosporium fulvum. Griffiths SA, Cox RJ, Overdijk EJR, Mesarich CH, Saccomanno B, Lazarus CM, de Wit PJGM, Collemare J. PLoS One 13 e0209600 (2018)


Reviews citing this publication (1)

  1. Proton Bridging in Catalysis by and Inhibition of Serine Proteases of the Blood Cascade System. Kovach IM. Life (Basel) 11 396 (2021)

Articles citing this publication (4)

  1. From natural to synthetic multisite thrombin inhibitors. Lombardi A, De Simone G, Galdiero S, Staiano N, Nastri F, Pavone V. Biopolymers 51 19-39 (1999)
  2. Branched porphyrins as functional scaffolds for multisite bioconjugation. Engelen M, Lombardi A, Vitale R, Lista L, Maglio O, Pavone V, Nastri F. Biotechnol Appl Biochem 62 383-392 (2015)
  3. Proton bridging in the interactions of thrombin with hirudin and its mimics. Kovach IM, Kakalis L, Jordan F, Zhang D. Biochemistry 52 2472-2481 (2013)
  4. Historical Article Vincenzo Pavone: Friend, mentor and inspiring scientist. Nastri F, Maglio O, Lombardi A. Biopolymers 109 e23234 (2018)


Related citations provided by authors (4)

  1. The Structure of a Complex of Recombinant Hirudin and Human Alpha-Thrombin. Rydel TJ, Ravichandran KG, Tulinsky A, Bode W, Huber R, Roitsch C, Fenton 2D JW Science 249 277- (1990)
  2. Hirunorms are True Hirudin Mimetics. The Crystal Structure of Human Alpha-Thrombin-Hirunorm V Complex. De Simone G, Lombardi A, Galdiero S, Nastri F, Della Morte R, Staiano N, Pedone C, Bolognesi M, Pavone V Protein Sci. 7 243- (1998)
  3. Rational Design of True Hirudin Mimetics: Synthesis and Characterization of Multisite-Directed Alpha-Thrombin Inhibitors. Lombardi A, Nastri F, Della Morte R, Rossi A, De Rosa A, Staiano N, Pedone C, Pavone V J. Med. Chem. 39 2008- (1996)
  4. Refined Structure of the Hirudin-Thrombin Complex. Rydel TJ, Tulinsky A, Bode W, Huber R J. Mol. Biol. 221 583- (1991)

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