5a8e: Difference between revisions
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==thermostabilised beta1-adrenoceptor with rationally designed inverse agonist 7-methylcyanopindolol bound== | ==thermostabilised beta1-adrenoceptor with rationally designed inverse agonist 7-methylcyanopindolol bound== | ||
<StructureSection load='5a8e' size='340' side='right' caption='[[5a8e]], [[Resolution|resolution]] 2.40Å' scene=''> | <StructureSection load='5a8e' size='340' side='right' caption='[[5a8e]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5a8e]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5A8E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5A8E FirstGlance]. <br> | <table><tr><td colspan='2'>[[5a8e]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Melga Melga]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5A8E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5A8E FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MHA:(CARBAMOYLMETHYL-CARBOXYMETHYL-AMINO)-ACETIC+ACID'>MHA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=XTK:4-[(2S)-3-(TERT-BUTYLAMINO)-2-HYDROXYPROPOXY]-7-METHYL-1H-INDOLE-2-CARBONITRILE'>XTK</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MHA:(CARBAMOYLMETHYL-CARBOXYMETHYL-AMINO)-ACETIC+ACID'>MHA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=XTK:4-[(2S)-3-(TERT-BUTYLAMINO)-2-HYDROXYPROPOXY]-7-METHYL-1H-INDOLE-2-CARBONITRILE'>XTK</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=5a8e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5a8e OCA], [http://pdbe.org/5a8e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5a8e RCSB], [http://www.ebi.ac.uk/pdbsum/5a8e 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=5a8e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5a8e OCA], [http://pdbe.org/5a8e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5a8e RCSB], [http://www.ebi.ac.uk/pdbsum/5a8e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5a8e ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Melga]] | |||
[[Category: Baker, J G]] | [[Category: Baker, J G]] | ||
[[Category: Brown, G A]] | [[Category: Brown, G A]] | ||
Revision as of 17:35, 16 November 2017
thermostabilised beta1-adrenoceptor with rationally designed inverse agonist 7-methylcyanopindolol boundthermostabilised beta1-adrenoceptor with rationally designed inverse agonist 7-methylcyanopindolol bound
Structural highlights
Function[ADRB1_MELGA] Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. This receptor binds epinephrine and norepinephrine with approximately equal affinity. Publication Abstract from PubMedComparisons between structures of the lower case beta1-adrenergic receptor (beta1AR) bound to either agonists, partial agonists or weak partial agonists led to the proposal that rotamer changes of Ser5.46, coupled to a contraction of the binding pocket, are sufficient to increase the probability of receptor activation. Cyanopindolol is a weak partial agonist of beta1AR and, based on the hypothesis above, we predicted that the addition of a methyl group to form 7-methylcyanopindolol would reduce dramatically its efficacy. An eight-step synthesis of 7-methylcyanopindolol was developed and its pharmacology analysed. 7-Methylcyanopindolol bound with similar affinity to cyanopindolol to both beta1AR and beta2AR. As predicted, the efficacy of 7-methylcyanopindolol was dramatically reduced compared to cyanopindolol, acting as a very weak partial of turkey beta1AR and an inverse agonist of human beta2AR. The structure of 7-methylcyanopindolol-bound beta1AR was determined to 2.4 A resolution and found to be virtually identical to the structure of cyanopindolol-bound beta1AR. The major differences in the orthosteric binding pocket are that it has expanded by 0.3 A in 7-methylcyanopoindol-bound beta1AR and the hydroxyl group of Ser5.46 is positioned 0.8 A further from the ligand with respect to the position of the Ser5.46 side chain in cyanopindolol-bound beta1AR. Thus the molecular basis for the reduction in efficacy of 7-methylcyanopindolol compared to cyanopindolol may be regarded as the opposite of the mechanism proposed for the increase in efficacy of agonists compared to antagonists. Pharmacological Analysis and Structure Determination of 7-Methylcyanopindolol-Bound beta1-Adrenergic Receptor.,Sato T, Baker J, Warne T, Brown G, Leslie A, Congreve M, Tate C Mol Pharmacol. 2015 Sep 18. pii: mol.115.101030. PMID:26385885[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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