1bx7
From Proteopedia
(New page: 200px<br /><applet load="1bx7" size="450" color="white" frame="true" align="right" spinBox="true" caption="1bx7, resolution 1.20Å" /> '''HIRUSTASIN FROM HIRU...) |
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| - | [[Image:1bx7.jpg|left|200px]]<br /><applet load="1bx7" size=" | + | [[Image:1bx7.jpg|left|200px]]<br /><applet load="1bx7" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1bx7, resolution 1.20Å" /> | caption="1bx7, resolution 1.20Å" /> | ||
'''HIRUSTASIN FROM HIRUDO MEDICINALIS AT 1.2 ANGSTROMS'''<br /> | '''HIRUSTASIN FROM HIRUDO MEDICINALIS AT 1.2 ANGSTROMS'''<br /> | ||
==Overview== | ==Overview== | ||
| - | BACKGROUND: Leech-derived inhibitors have a prominent role in the | + | 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== | ==About this Structure== | ||
| - | 1BX7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Hirudo_medicinalis Hirudo medicinalis] with SO4 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1BX7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Hirudo_medicinalis Hirudo medicinalis] with <scene name='pdbligand=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1BX7 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Bricogne, G.]] | [[Category: Bricogne, G.]] | ||
| - | [[Category: Fortelle, E | + | [[Category: Fortelle, E De La.]] |
| - | [[Category: Gruetter, M | + | [[Category: Gruetter, M G.]] |
| - | [[Category: Marco, S | + | [[Category: Marco, S Di.]] |
| - | [[Category: Mittl, P | + | [[Category: Mittl, P R.E.]] |
| - | [[Category: Priestle, J | + | [[Category: Priestle, J P.]] |
| - | [[Category: Sheldrick, G | + | [[Category: Sheldrick, G M.]] |
[[Category: Uson, I.]] | [[Category: Uson, I.]] | ||
[[Category: SO4]] | [[Category: SO4]] | ||
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[[Category: serine protease inhibitor]] | [[Category: serine protease inhibitor]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:00:05 2008'' |
Revision as of 10:00, 21 February 2008
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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 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
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