5m2v: Difference between revisions
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==Structure of GluK1 ligand-binding domain (S1S2) in complex with (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid at 3.18 A resolution== | |||
<StructureSection load='5m2v' size='340' side='right' caption='[[5m2v]], [[Resolution|resolution]] 3.18Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5m2v]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M2V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5M2V FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7E5:(2~{S},4~{R})-4-(2-CARBOXYPHENOXY)PYRROLIDINE-2-CARBOXYLIC+ACID'>7E5</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=5m2v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m2v OCA], [http://pdbe.org/5m2v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5m2v RCSB], [http://www.ebi.ac.uk/pdbsum/5m2v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5m2v ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/GRIK1_RAT GRIK1_RAT]] Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. May be involved in the transmission of light information from the retina to the hypothalamus.<ref>PMID:16540562</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (Ki = 4 muM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 +/- 2 muM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14 degrees was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor. | |||
Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid.,Krogsgaard-Larsen N, Delgar CG, Koch K, Brown PM, Moller C, Han L, Huynh TH, Hansen SW, Nielsen B, Bowie D, Pickering DS, Kastrup JS, Frydenvang K, Bunch L J Med Chem. 2017 Jan 12;60(1):441-457. doi: 10.1021/acs.jmedchem.6b01516. Epub, 2016 Dec 22. PMID:28005385<ref>PMID:28005385</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5m2v" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Frydenvang, K]] | [[Category: Frydenvang, K]] | ||
[[Category: Kastrup, J | [[Category: Kastrup, J S]] | ||
[[Category: Kristensen, C M]] | |||
[[Category: Antagonist]] | |||
[[Category: Gluk1-lbd]] | |||
[[Category: Gluk1-s1s2]] | |||
[[Category: Kainate receptor ligand-binding domain]] | |||
[[Category: Membrane protein]] | |||
