1bx7
From Proteopedia
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HIRUSTASIN FROM HIRUDO MEDICINALIS AT 1.2 ANGSTROMS
Overview
BACKGROUND: Leech-derived inhibitors have a prominent role in the, development of new antithrombotic drugs, because some of them are able to, block the blood coagulation cascade. Hirustasin, a serine protease, inhibitor from the leech Hirudo medicinalis, binds specifically to tissue, kallikrein and possesses structural similarity with antistasin, a potent, factor Xa inhibitor from Haementeria officinalis. Although the 2.4 A, structure of the hirustasin-kallikrein complex is known, classical methods, such as molecular replacement were not successful in solving the structure, of free hirustasin. RESULTS: Ab initio real/reciprocal space iteration has, been used to solve the structure of free hirustasin using either 1.4 A, room temperature data or 1.2 A low temperature diffraction data. The, structure was also solved independently from a single pseudo-symmetric, gold derivative using maximum likelihood methods. A comparison of the free, and complexed structures reveals that binding to kallikrein causes a, hinge-bending motion between the two hirustasin subdomains. This movement, is accompanied by the isomerisation of a cis proline to the trans, conformation and a movement of the P3, P4 and P5 residues so that they can, interact with the cognate protease. CONCLUSIONS: The inhibitors from this, protein family are fairly flexible despite being highly cross-linked by, disulphide bridges. This intrinsic flexibility is necessary to adopt a, conformation that is recognised by the protease and to achieve an optimal, fit, such observations illustrate the pitfalls of designing inhibitors, based on static lock-and-key models. This work illustrates the potential, of new methods of structure solution that require less or even no prior, phase information.
About this Structure
1BX7 is a Single protein structure of sequence from Hirudo medicinalis with SO4 as ligand. Full crystallographic information is available from OCA.
Reference
The 1.2 A crystal structure of hirustasin reveals the intrinsic flexibility of a family of highly disulphide-bridged inhibitors., Uson I, Sheldrick GM, de La Fortelle E, Bricogne G, Di Marco S, Priestle JP, Grutter MG, Mittl PR, Structure. 1999 Jan 15;7(1):55-63. PMID:10368273
Page seeded by OCA on Tue Nov 20 11:59:23 2007
