From Proteopedia
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| - | [[Image:1bx8.jpg|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_1bx8| PDB=1bx8 | SCENE= }} | | {{STRUCTURE_1bx8| PDB=1bx8 | SCENE= }} |
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| - | '''HIRUSTASIN FROM HIRUDO MEDICINALIS AT 1.4 ANGSTROMS'''
| + | ===HIRUSTASIN FROM HIRUDO MEDICINALIS AT 1.4 ANGSTROMS=== |
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| - | ==Overview==
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| - | 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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_10368273}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 10368273 is the PubMed ID number. |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Peptidic inhibitor]] | | [[Category: Peptidic inhibitor]] |
| | [[Category: Serine protease inhibitor]] | | [[Category: Serine protease inhibitor]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 12:04:19 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jun 30 19:51:41 2008'' |
Revision as of 16:51, 30 June 2008
Template:STRUCTURE 1bx8
HIRUSTASIN FROM HIRUDO MEDICINALIS AT 1.4 ANGSTROMS
Template:ABSTRACT PUBMED 10368273
About this Structure
1BX8 is a Single protein structure of sequence from Hirudo medicinalis. 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 Mon Jun 30 19:51:41 2008
