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5m2v

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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

Structural highlights

5m2v is a 2 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.18Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1]

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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Mayer ML, Ghosal A, Dolman NP, Jane DE. Crystal structures of the kainate receptor GluR5 ligand binding core dimer with novel GluR5-selective antagonists. J Neurosci. 2006 Mar 15;26(11):2852-61. PMID:16540562 doi:26/11/2852
↑ 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. 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. J Med Chem. 2017 Jan 12;60(1):441-457. doi: 10.1021/acs.jmedchem.6b01516. Epub, 2016 Dec 22. PMID:28005385 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01516

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5m2v"

Categories: Large Structures | Rattus norvegicus | Frydenvang K | Kastrup JS | Kristensen CM

@@ Line 1: / Line 1: @@
 ==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]] 3.18&Aring;' scene=''>
+<StructureSection load='5m2v' size='340' side='right'caption='[[5m2v]], [[Resolution|resolution]] 3.18&Aring;' 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>
+<table><tr><td colspan='2'>[[5m2v]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. 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 [https://proteopedia.org/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>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.18&#8491;</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>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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'>[https://proteopedia.org/fgij/fg.htm?mol=5m2v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m2v OCA], [https://pdbe.org/5m2v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5m2v RCSB], [https://www.ebi.ac.uk/pdbsum/5m2v PDBsum], [https://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>
+[https://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 ==
@@ Line 20: / Line 21: @@
 ==See Also==
-*[[Ionotropic Glutamate Receptors|Ionotropic Glutamate Receptors]]
+*[[Glutamate receptor 3D structures|Glutamate receptor 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Frydenvang, K]]
+[[Category: Large Structures]]
-[[Category: Kastrup, J S]]
+[[Category: Rattus norvegicus]]
-[[Category: Kristensen, C M]]
+[[Category: Frydenvang K]]
-[[Category: Antagonist]]
+[[Category: Kastrup JS]]
-[[Category: Gluk1-lbd]]
+[[Category: Kristensen CM]]
-[[Category: Gluk1-s1s2]]
-[[Category: Kainate receptor ligand-binding domain]]
-[[Category: Membrane protein]]

5m2v

From Proteopedia

Current revision

Structure of GluK1 ligand-binding domain (S1S2) in complex with (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid at 3.18 A resolution

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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