|
|
| (4 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| | + | |
| | ==Crystal structure of mutant Lys8Asp of scorpion alpha-like neurotoxin BmK M1 from Buthus martensii Karsch== | | ==Crystal structure of mutant Lys8Asp of scorpion alpha-like neurotoxin BmK M1 from Buthus martensii Karsch== |
| - | <StructureSection load='1t7a' size='340' side='right' caption='[[1t7a]], [[Resolution|resolution]] 1.50Å' scene=''> | + | <StructureSection load='1t7a' size='340' side='right'caption='[[1t7a]], [[Resolution|resolution]] 1.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1t7a]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mesobuthus_martensii Mesobuthus martensii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1T7A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1T7A FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1t7a]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mesobuthus_martensii Mesobuthus martensii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1T7A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1T7A FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1sn1|1sn1]], [[1t7b|1t7b]], [[1t7e|1t7e]]</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BmK M1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=34649 Mesobuthus martensii])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1t7a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1t7a OCA], [https://pdbe.org/1t7a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1t7a RCSB], [https://www.ebi.ac.uk/pdbsum/1t7a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1t7a ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1t7a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1t7a OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1t7a RCSB], [http://www.ebi.ac.uk/pdbsum/1t7a PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/SCX1_MESMA SCX1_MESMA]] This alpha-like toxin binds voltage-dependently sodium channels and inhibits the inactivation of the activated channels, thereby blocking neuronal transmission. This toxin is active against mammals and insects. Is active on Nav1.4/SCN4A and Nav1.5/SCN5A. Acts as a cardiotoxin. Is 6-fold more toxic than BmK-M2.<ref>PMID:11322948</ref> <ref>PMID:12705833</ref> | + | [https://www.uniprot.org/uniprot/SCM1_MESMA SCM1_MESMA] Alpha toxins bind voltage-independently at site-3 of sodium channels (Nav) and inhibit the inactivation of the activated channels thereby blocking neuronal transmission. This toxin is active against both mammals and insects, and is classified as an alpha-like toxin. It is active on Nav1.2/SCN2A (EC(50)=139-252 nM), Nav1.3/SCN3A (EC(50)=565 nM), Nav1.4/SCN4A and Nav1.5/SCN5A (EC(50)=195-500 nM), Nav1.6/SCN8A (EC(50)=214 nM), and drosophila DmNav1 (EC(50)=30 nM) (PubMed:11322948, PubMed:12705833, PubMed:15677695, PubMed:19162162, PubMed:20678086). In mNav1.6/SCN8A, the toxin induces a large increase in both transient and persistent currents, which correlates with a prominent reduction in the fast component of inactivating current (PubMed:20678086). In rNav1.2/SCN2A and rNav1.3/SCN3A, toxin-increased currents is much smaller (PubMed:19162162, PubMed:20678086). Moreover, the toxin only accelerates the slow inactivation development and delay recovery of mNav1.6/SCN8A through binding to the channel in the open state (PubMed:20678086). Is 6-fold more toxic than BmK-M2. In vivo, intrahippocampal injection into rat induces epileptiform responses (PubMed:16229835). In addition, intraplantar injection into rat induces spontaneous nociception and hyperalgesia (PubMed:14554105).<ref>PMID:11322948</ref> <ref>PMID:12705833</ref> <ref>PMID:14554105</ref> <ref>PMID:15677695</ref> <ref>PMID:16229835</ref> <ref>PMID:19162162</ref> <ref>PMID:20678086</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/t7/1t7a_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/t7/1t7a_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
| - | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1t7a ConSurf]. |
| | <div style="clear:both"></div> | | <div style="clear:both"></div> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| Line 27: |
Line 27: |
| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 1t7a" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Large Structures]] |
| | [[Category: Mesobuthus martensii]] | | [[Category: Mesobuthus martensii]] |
| - | [[Category: Guan, R J]] | + | [[Category: Guan RJ]] |
| - | [[Category: He, X L]] | + | [[Category: He XL]] |
| - | [[Category: Sundberg, E J]] | + | [[Category: Sundberg EJ]] |
| - | [[Category: Wang, C G]] | + | [[Category: Wang CG]] |
| - | [[Category: Wang, D C]] | + | [[Category: Wang DC]] |
| - | [[Category: Wang, M]] | + | [[Category: Wang M]] |
| - | [[Category: Xiang, Y]] | + | [[Category: Xiang Y]] |
| - | [[Category: Zhang, Y]] | + | [[Category: Zhang Y]] |
| - | [[Category: Cis/trans isomerization]]
| + | |
| - | [[Category: Intramolecular switch]]
| + | |
| - | [[Category: Non-proline peptide bond]]
| + | |
| - | [[Category: Scorpion toxin]]
| + | |
| - | [[Category: Toxin]]
| + | |
| Structural highlights
Function
SCM1_MESMA Alpha toxins bind voltage-independently at site-3 of sodium channels (Nav) and inhibit the inactivation of the activated channels thereby blocking neuronal transmission. This toxin is active against both mammals and insects, and is classified as an alpha-like toxin. It is active on Nav1.2/SCN2A (EC(50)=139-252 nM), Nav1.3/SCN3A (EC(50)=565 nM), Nav1.4/SCN4A and Nav1.5/SCN5A (EC(50)=195-500 nM), Nav1.6/SCN8A (EC(50)=214 nM), and drosophila DmNav1 (EC(50)=30 nM) (PubMed:11322948, PubMed:12705833, PubMed:15677695, PubMed:19162162, PubMed:20678086). In mNav1.6/SCN8A, the toxin induces a large increase in both transient and persistent currents, which correlates with a prominent reduction in the fast component of inactivating current (PubMed:20678086). In rNav1.2/SCN2A and rNav1.3/SCN3A, toxin-increased currents is much smaller (PubMed:19162162, PubMed:20678086). Moreover, the toxin only accelerates the slow inactivation development and delay recovery of mNav1.6/SCN8A through binding to the channel in the open state (PubMed:20678086). Is 6-fold more toxic than BmK-M2. In vivo, intrahippocampal injection into rat induces epileptiform responses (PubMed:16229835). In addition, intraplantar injection into rat induces spontaneous nociception and hyperalgesia (PubMed:14554105).[1] [2] [3] [4] [5] [6] [7]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Non-proline cis peptide bonds have been observed in numerous protein crystal structures even though the energetic barrier to this conformation is significant and no non-prolyl-cis/trans-isomerase has been identified to date. While some external factors, such as metal binding or co-factor interaction, have been identified that appear to induce cis/trans isomerization of non-proline peptide bonds, the intrinsic structural basis for their existence and the mechanism governing cis/trans isomerization in proteins remains poorly understood. Here, we report the crystal structure of a newly isolated neurotoxin, the scorpion alpha-like toxin Buthus martensii Karsch (BmK) M7, at 1.4A resolution. BmK M7 crystallizes as a dimer in which the identical non-proline peptide bond between residues 9 and 10 exists either in the cis conformation or as a mixture of cis and trans conformations in either monomer. We also determined the crystal structures of several mutants of BmK M1, a representative scorpion alpha-like toxin that contains an identical non-proline cis peptide bond as that observed in BmK M7, in which residues within or neighboring the cis peptide bond were altered. Substitution of an aspartic acid residue for lysine at residue 8 in the BmK M1 (K8D) mutant converted the cis form of the non-proline peptide bond 9-10 into the trans form, revealing an intramolecular switch for cis-to-trans isomerization. Cis/trans interconversion of the switch residue at position 8 appears to be sequence-dependent as the peptide bond between residues 9 and 10 retains its wild-type cis conformation in the BmK M1 (K8Q) mutant structure. The structural interconversion of the isomeric states of the BmK M1 non-proline cis peptide bond may relate to the conversion of the scorpion alpha-toxins subgroups.
Structural mechanism governing cis and trans isomeric states and an intramolecular switch for cis/trans isomerization of a non-proline peptide bond observed in crystal structures of scorpion toxins.,Guan RJ, Xiang Y, He XL, Wang CG, Wang M, Zhang Y, Sundberg EJ, Wang DC J Mol Biol. 2004 Aug 27;341(5):1189-204. PMID:15321715[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Goudet C, Huys I, Clynen E, Schoofs L, Wang DC, Waelkens E, Tytgat J. Electrophysiological characterization of BmK M1, an alpha-like toxin from Buthus martensi Karsch venom. FEBS Lett. 2001 Apr 20;495(1-2):61-5. PMID:11322948
- ↑ Wang CG, Gilles N, Hamon A, Le Gall F, Stankiewicz M, Pelhate M, Xiong YM, Wang DC, Chi CW. Exploration of the functional site of a scorpion alpha-like toxin by site-directed mutagenesis. Biochemistry. 2003 Apr 29;42(16):4699-708. PMID:12705833 doi:http://dx.doi.org/10.1021/bi0270438
- ↑ Bai ZT, Zhang XY, Ji YH. Fos expression in rat spinal cord induced by peripheral injection of BmK I, an alpha-like scorpion neurotoxin. Toxicol Appl Pharmacol. 2003 Oct 1;192(1):78-85. PMID:14554105 doi:10.1016/s0041-008x(03)00260-6
- ↑ Liu LH, Bosmans F, Maertens C, Zhu RH, Wang DC, Tytgat J. Molecular basis of the mammalian potency of the scorpion alpha-like toxin, BmK M1. FASEB J. 2005 Apr;19(6):594-6. PMID:15677695 doi:10.1096/fj.04-2485fje
- ↑ Bai ZT, Zhao R, Zhang XY, Chen J, Liu T, Ji YH. The epileptic seizures induced by BmK I, a modulator of sodium channels. Exp Neurol. 2006 Jan;197(1):167-76. PMID:16229835 doi:10.1016/j.expneurol.2005.09.006
- ↑ Zhu MM, Tan M, Cheng HW, Ji YH. The alpha-like scorpion toxin BmK I enhances membrane excitability via persistent sodium current by preventing slow inactivation and deactivation of rNav1.2a expressed in Xenopus Oocytes. Toxicol In Vitro. 2009 Jun;23(4):561-8. PMID:19162162 doi:10.1016/j.tiv.2008.12.022
- ↑ He H, Liu Z, Dong B, Zhou J, Zhu H, Ji Y. Molecular determination of selectivity of the site 3 modulator (BmK I) to sodium channels in the CNS: a clue to the importance of Nav1.6 in BmK I-induced neuronal hyperexcitability. Biochem J. 2010 Oct 15;431(2):289-98. PMID:20678086 doi:10.1042/BJ20100517
- ↑ Guan RJ, Xiang Y, He XL, Wang CG, Wang M, Zhang Y, Sundberg EJ, Wang DC. Structural mechanism governing cis and trans isomeric states and an intramolecular switch for cis/trans isomerization of a non-proline peptide bond observed in crystal structures of scorpion toxins. J Mol Biol. 2004 Aug 27;341(5):1189-204. PMID:15321715 doi:http://dx.doi.org/10.1016/j.jmb.2004.06.067
|
