1xtf
From Proteopedia
(New page: 200px<br /><applet load="1xtf" size="450" color="white" frame="true" align="right" spinBox="true" caption="1xtf, resolution 2.2Å" /> '''neurotoxin BoNT/A E22...) |
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| - | [[Image:1xtf.gif|left|200px]]<br /><applet load="1xtf" size=" | + | [[Image:1xtf.gif|left|200px]]<br /><applet load="1xtf" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1xtf, resolution 2.2Å" /> | caption="1xtf, resolution 2.2Å" /> | ||
'''neurotoxin BoNT/A E224Q Y366F mutant'''<br /> | '''neurotoxin BoNT/A E224Q Y366F mutant'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Clostridal neurotoxins (CNTs) are the causative agents of the | + | Clostridal neurotoxins (CNTs) are the causative agents of the neuroparalytic diseases botulism and tetanus. CNTs impair neuronal exocytosis through specific proteolysis of essential proteins called SNAREs. SNARE assembly into a low-energy ternary complex is believed to catalyse membrane fusion, precipitating neurotransmitter release; this process is attenuated in response to SNARE proteolysis. Site-specific SNARE hydrolysis is catalysed by the CNT light chains, a unique group of zinc-dependent endopeptidases. The means by which a CNT properly identifies and cleaves its target SNARE has been a subject of much speculation; it is thought to use one or more regions of enzyme-substrate interaction remote from the active site (exosites). Here we report the first structure of a CNT endopeptidase in complex with its target SNARE at a resolution of 2.1 A: botulinum neurotoxin serotype A (BoNT/A) protease bound to human SNAP-25. The structure, together with enzyme kinetic data, reveals an array of exosites that determine substrate specificity. Substrate orientation is similar to that of the general zinc-dependent metalloprotease thermolysin. We observe significant structural changes near the toxin's catalytic pocket upon substrate binding, probably serving to render the protease competent for catalysis. The novel structures of the substrate-recognition exosites could be used for designing inhibitors specific to BoNT/A. |
==About this Structure== | ==About this Structure== | ||
| - | 1XTF is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Clostridium_botulinum Clostridium botulinum] with ZN as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1XTF is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Clostridium_botulinum Clostridium botulinum] with <scene name='pdbligand=ZN:'>ZN</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XTF OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Clostridium botulinum]] | [[Category: Clostridium botulinum]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Breidenbach, M | + | [[Category: Breidenbach, M A.]] |
| - | [[Category: Brunger, A | + | [[Category: Brunger, A T.]] |
[[Category: ZN]] | [[Category: ZN]] | ||
[[Category: botulism]] | [[Category: botulism]] | ||
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[[Category: zinc endopeptidase]] | [[Category: zinc endopeptidase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:58:31 2008'' |
Revision as of 13:58, 21 February 2008
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neurotoxin BoNT/A E224Q Y366F mutant
Overview
Clostridal neurotoxins (CNTs) are the causative agents of the neuroparalytic diseases botulism and tetanus. CNTs impair neuronal exocytosis through specific proteolysis of essential proteins called SNAREs. SNARE assembly into a low-energy ternary complex is believed to catalyse membrane fusion, precipitating neurotransmitter release; this process is attenuated in response to SNARE proteolysis. Site-specific SNARE hydrolysis is catalysed by the CNT light chains, a unique group of zinc-dependent endopeptidases. The means by which a CNT properly identifies and cleaves its target SNARE has been a subject of much speculation; it is thought to use one or more regions of enzyme-substrate interaction remote from the active site (exosites). Here we report the first structure of a CNT endopeptidase in complex with its target SNARE at a resolution of 2.1 A: botulinum neurotoxin serotype A (BoNT/A) protease bound to human SNAP-25. The structure, together with enzyme kinetic data, reveals an array of exosites that determine substrate specificity. Substrate orientation is similar to that of the general zinc-dependent metalloprotease thermolysin. We observe significant structural changes near the toxin's catalytic pocket upon substrate binding, probably serving to render the protease competent for catalysis. The novel structures of the substrate-recognition exosites could be used for designing inhibitors specific to BoNT/A.
About this Structure
1XTF is a Single protein structure of sequence from Clostridium botulinum with as ligand. Full crystallographic information is available from OCA.
Reference
Substrate recognition strategy for botulinum neurotoxin serotype A., Breidenbach MA, Brunger AT, Nature. 2004 Dec 16;432(7019):925-9. Epub 2004 Dec 12. PMID:15592454
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