1AD8

COMPLEX OF THROMBIN WITH AND INHIBITOR CONTAINING A NOVEL P1 MOIETY

1AD8 の概要

• エントリーDOI: 10.2210/pdb1ad8/pdb
• 分子名称: THROMBIN (SMALL SUBUNIT), THROMBIN (LARGE SUBUNIT), HIRUDIN (53-65) PEPTIDE, ... (6 entities in total)
• 機能のキーワード: complex (serine protease-inhibitor), hydrolase, serine protease, coagulant, inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Hirudo medicinalis (medicinal leech); 詳細
• 細胞内の位置: Secreted, extracellular space: P00734 P00734; Secreted: P01050
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 35827.69

構造登録者

Schreuder, H.,Tardif, C.,Malikayil, J.A. (登録日: 1997-02-24, 公開日: 1997-11-12, 最終更新日: 2024-10-30)

主引用文献

Malikayil, J.A.,Burkhart, J.P.,Schreuder, H.A.,Broersma Jr., R.J.,Tardif, C.,Kutcher 3rd., L.W.,Mehdi, S.,Schatzman, G.L.,Neises, B.,Peet, N.P.
Molecular design and characterization of an alpha-thrombin inhibitor containing a novel P1 moiety.
Biochemistry, 36:1034-1040, 1997

PubMed Abstract: An inhibitor of alpha-thrombin was designed on the basis of the X-ray crystal structures of thrombin and trypsin. The design strategy employed the geometric and electrostatic differences between the specificity pockets of the two enzymes. These differences arise due to the replacement of Ser 190 in trypsin by Ala 190 in thrombin. The new inhibitor contained a tryptophan side chain instead of the arginine side chain that is present in the prototypical thrombin inhibitors. This inhibitor had a Ki value of 0.25 microM, displayed more than 400-fold specificity for thrombin over trypsin, and doubled the rat plasma APTT at a concentration of 44.9 microM. The X-ray crystal structure of the inhibitor/alpha-thrombin complex was determined. This represents the first reported three-dimensional structure of a thrombin/ inhibitor complex where the specificity pocket of the enzyme is occupied by a chemical moiety other than a guanidino or an amidino group. As was predicted by the molecular model, the tryptophan side chain docks into the specificity pocket of the enzyme. This finding is in contrast with the indole binding region of thrombin reported earlier [Berliner, L. J., & Shen, Y. Y. L. (1977) Biochemistry 16, 4622-4626]. The lower binding affinity of the new inhibitor for trypsin, compared to that for thrombin, appears to be due to (i) the extra energy required to deform the smaller specificity pocket of trypsin to accommodate the bulky indole group and (ii) the favorable electrostatic interactions of the indole group with the more hydrophobic specificity pocket of thrombin. The neutral indole group may be of pharmacological significance because the severe hypotension and respiratory distress observed following the administration of some thrombin inhibitors have been linked to the positively charged guanidino or amidino functionalities.

PubMed: 9033393
DOI: 10.1021/bi9622231

実験手法

X-RAY DIFFRACTION (2 Å)