2hpp

From Proteopedia

Revision as of 15:33, 15 February 2008

STRUCTURES OF THE NONCOVALENT COMPLEXES OF HUMAN AND BOVINE PROTHROMBIN FRAGMENT 2 WITH HUMAN PPACK-THROMBIN

Overview

Both human and bovine prothrombin fragment 2 (the second kringle) have, been cocrystallized separately with human PPACK (D-Phe-Pro-Arg)-thrombin, and the structures of these noncovalent complexes have been determined and, refined (R = 0.155 and 0.157, respectively) at 3.3-A resolution using, X-ray crystallographic methods. The kringles interact with thrombin at a, site that has previously been proposed to be the heparin binding region., The latter is a highly electropositive surface near the C-terminal helix, of thrombin abundant in arginine and lysine residues. These form salt, bridges with acidic side chains of kringle 2. Somewhat unexpectedly, the, negative groups of the kringle correspond to an enlarged anionic center of, the lysine binding site of lysine binding kringles such as plasminogens K1, and K4 and TPA K2. The anionic motif is DGDEE in prothrombin kringle 2., The corresponding cationic center of the lysine binding site region has an, unfavorable Arg70Asp substitution, but Lys35 is conserved. However, the, folding of fragment 2 is different from that of prothrombin kringle 1 and, other kringles: the second outer loop possesses a distorted two-turn, helix, and the hairpin beta-turn of the second inner loop pivots at Val64, and Asp70 by 60 degrees. Lys35 is located on a turn of the helix, which, causes it to project into solvent space in the fragment 2-thrombin, complex, thereby devastating any vestige of the cationic center of the, lysine binding site. Since fragment 2 has not been reported to bind, lysine, it most likely has a different inherent folding conformation for, the second outer loop, as has also been observed to be the case with TPA, K2 and the urokinase kringle. The movement of the Val64-Asp70 beta-turn is, most likely a conformational change accompanying complexation, which, reveals a new heretofore unsuspected flexibility in kringles. The fragment, 2-thrombin complex is only the second cassette module-catalytic domain, structure to be determined for a multidomain blood protein and only the, third domain-domain interaction to be described among such proteins, the, others being factor Xa without a Gla domain and Ca2+ prothrombin fragment, 1 with a Gla domain and a kringle.

Disease

Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]

About this Structure

2HPP is a Protein complex structure of sequences from Homo sapiens with as ligand. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.

Reference

Structures of the noncovalent complexes of human and bovine prothrombin fragment 2 with human PPACK-thrombin., Arni RK, Padmanabhan K, Padmanabhan KP, Wu TP, Tulinsky A, Biochemistry. 1993 May 11;32(18):4727-37. PMID:8387813

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