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2nm1
From Proteopedia
(New page: 200px<br /><applet load="2nm1" size="450" color="white" frame="true" align="right" spinBox="true" caption="2nm1, resolution 2.15Å" /> '''Structure of BoNT/B ...) |
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| - | [[Image:2nm1.gif|left|200px]]<br /><applet load="2nm1" size=" | + | [[Image:2nm1.gif|left|200px]]<br /><applet load="2nm1" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2nm1, resolution 2.15Å" /> | caption="2nm1, resolution 2.15Å" /> | ||
'''Structure of BoNT/B in complex with its protein receptor'''<br /> | '''Structure of BoNT/B in complex with its protein receptor'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Botulinum neurotoxins (BoNTs) are produced by Clostridium botulinum and | + | Botulinum neurotoxins (BoNTs) are produced by Clostridium botulinum and cause the neuroparalytic syndrome of botulism. With a lethal dose of 1 ng kg(-1), they pose a biological hazard to humans and a serious potential bioweapon threat. BoNTs bind with high specificity at neuromuscular junctions and they impair exocytosis of synaptic vesicles containing acetylcholine through specific proteolysis of SNAREs (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors), which constitute part of the synaptic vesicle fusion machinery. The molecular details of the toxin-cell recognition have been elusive. Here we report the structure of a BoNT in complex with its protein receptor: the receptor-binding domain of botulinum neurotoxin serotype B (BoNT/B) bound to the luminal domain of synaptotagmin II, determined at 2.15 A resolution. On binding, a helix is induced in the luminal domain which binds to a saddle-shaped crevice on a distal tip of BoNT/B. This crevice is adjacent to the non-overlapping ganglioside-binding site of BoNT/B. Synaptotagmin II interacts with BoNT/B with nanomolar affinity, at both neutral and acidic endosomal pH. Biochemical and neuronal ex vivo studies of structure-based mutations indicate high specificity and affinity of the interaction, and high selectivity of BoNT/B among synaptotagmin I and II isoforms. Synergistic binding of both synaptotagmin and ganglioside imposes geometric restrictions on the initiation of BoNT/B translocation after endocytosis. Our results provide the basis for the rational development of preventive vaccines or inhibitors against these neurotoxins. |
==About this Structure== | ==About this Structure== | ||
| - | 2NM1 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Clostridium_botulinum Clostridium botulinum] and [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Active as [http://en.wikipedia.org/wiki/Bontoxilysin Bontoxilysin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.69 3.4.24.69] Full crystallographic information is available from [http:// | + | 2NM1 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Clostridium_botulinum Clostridium botulinum] and [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Active as [http://en.wikipedia.org/wiki/Bontoxilysin Bontoxilysin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.69 3.4.24.69] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2NM1 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Binz, T.]] | [[Category: Binz, T.]] | ||
| - | [[Category: Brunger, A | + | [[Category: Brunger, A T.]] |
[[Category: Jin, R.]] | [[Category: Jin, R.]] | ||
[[Category: Rummel, A.]] | [[Category: Rummel, A.]] | ||
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[[Category: synaptotagmin]] | [[Category: synaptotagmin]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:08:23 2008'' |
Revision as of 16:08, 21 February 2008
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Structure of BoNT/B in complex with its protein receptor
Overview
Botulinum neurotoxins (BoNTs) are produced by Clostridium botulinum and cause the neuroparalytic syndrome of botulism. With a lethal dose of 1 ng kg(-1), they pose a biological hazard to humans and a serious potential bioweapon threat. BoNTs bind with high specificity at neuromuscular junctions and they impair exocytosis of synaptic vesicles containing acetylcholine through specific proteolysis of SNAREs (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors), which constitute part of the synaptic vesicle fusion machinery. The molecular details of the toxin-cell recognition have been elusive. Here we report the structure of a BoNT in complex with its protein receptor: the receptor-binding domain of botulinum neurotoxin serotype B (BoNT/B) bound to the luminal domain of synaptotagmin II, determined at 2.15 A resolution. On binding, a helix is induced in the luminal domain which binds to a saddle-shaped crevice on a distal tip of BoNT/B. This crevice is adjacent to the non-overlapping ganglioside-binding site of BoNT/B. Synaptotagmin II interacts with BoNT/B with nanomolar affinity, at both neutral and acidic endosomal pH. Biochemical and neuronal ex vivo studies of structure-based mutations indicate high specificity and affinity of the interaction, and high selectivity of BoNT/B among synaptotagmin I and II isoforms. Synergistic binding of both synaptotagmin and ganglioside imposes geometric restrictions on the initiation of BoNT/B translocation after endocytosis. Our results provide the basis for the rational development of preventive vaccines or inhibitors against these neurotoxins.
About this Structure
2NM1 is a Single protein structure of sequence from Clostridium botulinum and Rattus norvegicus. Active as Bontoxilysin, with EC number 3.4.24.69 Full crystallographic information is available from OCA.
Reference
Botulinum neurotoxin B recognizes its protein receptor with high affinity and specificity., Jin R, Rummel A, Binz T, Brunger AT, Nature. 2006 Dec 21;444(7122):1092-5. Epub 2006 Dec 13. PMID:17167421
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