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[[ | ==Crystal structure of a mutant binding protein (5HTBP-AChBP) in complex with granisetron== | ||
<StructureSection load='2yme' size='340' side='right' caption='[[2yme]], [[Resolution|resolution]] 2.40Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2yme]] is a 10 chain structure with sequence from [http://en.wikipedia.org/wiki/Aplysia_californica Aplysia californica]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YME OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2YME FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CWB:1-METHYL-N-[(1R,5S)-9-METHYL-9-AZABICYCLO[3.3.1]NONAN-3-YL]INDAZOLE-3-CARBOXAMIDE'>CWB</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2ymd|2ymd]]</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=2yme FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yme OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2yme RCSB], [http://www.ebi.ac.uk/pdbsum/2yme PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The 5-HT3 receptor is a pentameric serotonin-gated ion channel, which mediates rapid excitatory neurotransmission and is the target of a therapeutically important class of anti-emetic drugs, such as granisetron. We report crystal structures of a binding protein engineered to recognize the agonist serotonin and the antagonist granisetron with affinities comparable to the 5-HT3 receptor. In the serotonin-bound structure, we observe hydrophilic interactions with loop E-binding site residues, which might enable transitions to channel opening. In the granisetron-bound structure, we observe a critical cation-pi interaction between the indazole moiety of the ligand and a cationic centre in loop D, which is uniquely present in the 5-HT3 receptor. We use a series of chemically tuned granisetron analogues to demonstrate the energetic contribution of this electrostatic interaction to high-affinity ligand binding in the human 5-HT3 receptor. Our study offers the first structural perspective on recognition of serotonin and antagonism by anti-emetics in the 5-HT3 receptor. | |||
Structural basis of ligand recognition in 5-HT3 receptors.,Kesters D, Thompson AJ, Brams M, van Elk R, Spurny R, Geitmann M, Villalgordo JM, Guskov A, Helena Danielson U, Lummis SC, Smit AB, Ulens C EMBO Rep. 2012 Nov 30. doi: 10.1038/embor.2012.189. PMID:23196367<ref>PMID:23196367</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
== | __TOC__ | ||
</StructureSection> | |||
[[Category: Aplysia californica]] | [[Category: Aplysia californica]] | ||
[[Category: Brams, M | [[Category: Brams, M]] | ||
[[Category: Danielson, U H | [[Category: Danielson, U H]] | ||
[[Category: Elk, R V | [[Category: Elk, R V]] | ||
[[Category: Geitmann, M | [[Category: Geitmann, M]] | ||
[[Category: Guskov, A | [[Category: Guskov, A]] | ||
[[Category: Kesters, D | [[Category: Kesters, D]] | ||
[[Category: Lummis, S C.R | [[Category: Lummis, S C.R]] | ||
[[Category: Smit, A B | [[Category: Smit, A B]] | ||
[[Category: Spurny, R | [[Category: Spurny, R]] | ||
[[Category: Thompson, A J | [[Category: Thompson, A J]] | ||
[[Category: Ulens, C | [[Category: Ulens, C]] | ||
[[Category: Villalgordo, J M | [[Category: Villalgordo, J M]] | ||
[[Category: Pentameric ligand-gated ion channel]] | [[Category: Pentameric ligand-gated ion channel]] | ||
[[Category: Receptor]] | [[Category: Receptor]] | ||
Revision as of 12:38, 15 February 2015
Crystal structure of a mutant binding protein (5HTBP-AChBP) in complex with granisetronCrystal structure of a mutant binding protein (5HTBP-AChBP) in complex with granisetron
Structural highlights
Publication Abstract from PubMedThe 5-HT3 receptor is a pentameric serotonin-gated ion channel, which mediates rapid excitatory neurotransmission and is the target of a therapeutically important class of anti-emetic drugs, such as granisetron. We report crystal structures of a binding protein engineered to recognize the agonist serotonin and the antagonist granisetron with affinities comparable to the 5-HT3 receptor. In the serotonin-bound structure, we observe hydrophilic interactions with loop E-binding site residues, which might enable transitions to channel opening. In the granisetron-bound structure, we observe a critical cation-pi interaction between the indazole moiety of the ligand and a cationic centre in loop D, which is uniquely present in the 5-HT3 receptor. We use a series of chemically tuned granisetron analogues to demonstrate the energetic contribution of this electrostatic interaction to high-affinity ligand binding in the human 5-HT3 receptor. Our study offers the first structural perspective on recognition of serotonin and antagonism by anti-emetics in the 5-HT3 receptor. Structural basis of ligand recognition in 5-HT3 receptors.,Kesters D, Thompson AJ, Brams M, van Elk R, Spurny R, Geitmann M, Villalgordo JM, Guskov A, Helena Danielson U, Lummis SC, Smit AB, Ulens C EMBO Rep. 2012 Nov 30. doi: 10.1038/embor.2012.189. PMID:23196367[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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