1TMU

Changes in interactions in complexes of hirudin derivatives and human alpha-thrombin due to different crystal forms

Summary for 1TMU

• Entry DOI: 10.2210/pdb1tmu/pdb
• Related: 1TMT
• Related PRD ID: PRD_000020
• Descriptor: Thrombin light chain, Thrombin heavy chain, Hirudin variant-2, ... (6 entities in total)
• Functional Keywords: serine protease, ppack inhibitor, blood coagulation, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 35264.68

Authors

Priestle, J.P.,Gruetter, M.G. (deposition date: 1994-05-26, release date: 1994-09-30, Last modification date: 2024-10-23)

Primary citation

Priestle, J.P.,Rahuel, J.,Rink, H.,Tones, M.,Grutter, M.G.
Changes in interactions in complexes of hirudin derivatives and human alpha-thrombin due to different crystal forms.
Protein Sci., 2:1630-1642, 1993

PubMed Abstract: The three-dimensional structures of D-Phe-Pro-Arg-chloromethyl ketone-inhibited thrombin in complex with Tyr-63-sulfated hirudin (ternary complex) and of thrombin in complex with the bifunctional inhibitor D-Phe-Pro-Arg-Pro-(Gly)4-hirudin (CGP 50,856, binary complex) have been determined by X-ray crystallography in crystal forms different from those described by Skrzypczak-Jankun et al. (Skrzypczak-Jankun, E., Carperos, V.E., Ravichandran, K.G., & Tulinsky, A., 1991, J. Mol. Biol. 221, 1379-1393). In both complexes, the interactions of the C-terminal hirudin segments of the inhibitors binding to the fibrinogen-binding exosite of thrombin are clearly established, including residues 60-64, which are disordered in the earlier crystal form. The interactions of the sulfate group of Tyr-63 in the ternary complex structure explain why natural sulfated hirudin binds with a 10-fold lower K(i) than the desulfated recombinant material. In this new crystal form, the autolysis loop of thrombin (residues 146-150), which is disordered in the earlier crystal form, is ordered due to crystal contacts. Interactions between the C-terminal fragment of hirudin and thrombin are not influenced by crystal contacts in this new crystal form, in contrast to the earlier form. In the bifunctional inhibitor-thrombin complex, the peptide bond between Arg-Pro (P1-P1') seems to be cleaved.

PubMed: 8251938

Experimental method

X-RAY DIFFRACTION (2.5 Å)