3fev: Difference between revisions
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==Crystal structure of the chimeric muscarinic toxin MT7 with loop 1 from MT1.== | ==Crystal structure of the chimeric muscarinic toxin MT7 with loop 1 from MT1.== | ||
<StructureSection load='3fev' size='340' side='right' caption='[[3fev]], [[Resolution|resolution]] 1.30Å' scene=''> | <StructureSection load='3fev' size='340' side='right' caption='[[3fev]], [[Resolution|resolution]] 1.30Å' scene=''> | ||
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2vlw|2vlw]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2vlw|2vlw]]</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=3fev FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fev OCA], [http://pdbe.org/3fev PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3fev RCSB], [http://www.ebi.ac.uk/pdbsum/3fev PDBsum]</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=3fev FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fev OCA], [http://pdbe.org/3fev PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3fev RCSB], [http://www.ebi.ac.uk/pdbsum/3fev PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3fev ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
Revision as of 12:45, 3 August 2017
Crystal structure of the chimeric muscarinic toxin MT7 with loop 1 from MT1.Crystal structure of the chimeric muscarinic toxin MT7 with loop 1 from MT1.
Structural highlights
Function[TXM1_DENAN] Binds irreversibly to M1 (CHRM1) muscarinic acetylcholine receptors, and reveals a slightly weaker effect at M3 (CHRM3) receptor. 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 PubMedProtein engineering approaches are often a combination of rational design and directed evolution using display technologies. Here, we test "loop grafting," a rational design method, on three-finger fold proteins. These small reticulated proteins have exceptional affinity and specificity for their diverse molecular targets, display protease-resistance, and are highly stable and poorly immunogenic. The wealth of structural knowledge makes them good candidates for protein engineering of new functionality. Our goal is to enhance the efficacy of these mini-proteins by modifying their pharmacological properties in order to extend their use in imaging, diagnostics and therapeutic applications. Using the interaction of three-finger fold toxins with muscarinic and adrenergic receptors as a model, chimeric toxins have been engineered by substituting loops on toxin MT7 by those from toxin MT1. The pharmacological impact of these grafts was examined using binding experiments on muscarinic receptors M1 and M4 and on the alpha(1A)-adrenoceptor. Some of the designed chimeric proteins have impressive gain of function on certain receptor subtypes achieving an original selectivity profile with high affinity for muscarinic receptor M1 and alpha(1A)-adrenoceptor. Structure-function analysis supported by crystallographic data for MT1 and two chimeras permits a molecular based interpretation of these gains and details the merits of this protein engineering technique. The results obtained shed light on how loop permutation can be used to design new three-finger proteins with original pharmacological profiles. Engineering of three-finger fold toxins creates ligands with original pharmacological profiles for muscarinic and adrenergic receptors.,Fruchart-Gaillard C, Mourier G, Blanchet G, Vera L, Gilles N, Menez R, Marcon E, Stura EA, Servent D PLoS One. 2012;7(6):e39166. Epub 2012 Jun 14. PMID:22720062[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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