View source for 7xka


==Structure of human beta2 adrenergic receptor bound to constrained epinephrine==
<StructureSection load='7xka' size='340' side='right'caption='[[7xka]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7xka]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_virus_T4 Escherichia virus T4] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7XKA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7XKA FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.1&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G1I:(5~{R},6~{R})-6-(methylamino)-5,6,7,8-tetrahydronaphthalene-1,2,5-triol'>G1I</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=7xka FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7xka OCA], [https://pdbe.org/7xka PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7xka RCSB], [https://www.ebi.ac.uk/pdbsum/7xka PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7xka ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/ADRB2_HUMAN ADRB2_HUMAN] Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. The beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine.[https://www.uniprot.org/uniprot/ENLYS_BPT4 ENLYS_BPT4] Endolysin with lysozyme activity that degrades host peptidoglycans and participates with the holin and spanin proteins in the sequential events which lead to the programmed host cell lysis releasing the mature viral particles. Once the holin has permeabilized the host cell membrane, the endolysin can reach the periplasm and break down the peptidoglycan layer.<ref>PMID:22389108</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
G protein-coupled receptors (GPCRs) within the same subfamily often share high homology in their orthosteric pocket and therefore pose challenges to drug development. The amino acids that form the orthosteric binding pocket for epinephrine and norepinephrine in the beta(1) and beta(2) adrenergic receptors (beta(1)AR and beta(2)AR) are identical. Here, to examine the effect of conformational restriction on ligand binding kinetics, we synthesized a constrained form of epinephrine. Surprisingly, the constrained epinephrine exhibits over 100-fold selectivity for the beta(2)AR over the beta(1)AR. We provide evidence that the selectivity may be due to reduced ligand flexibility that enhances the association rate for the beta(2)AR, as well as a less stable binding pocket for constrained epinephrine in the beta(1)AR. The differences in the amino acid sequence of the extracellular vestibule of the beta(1)AR allosterically alter the shape and stability of the binding pocket, resulting in a marked difference in affinity compared to the beta(2)AR. These studies suggest that for receptors containing identical binding pocket residues, the binding selectivity may be influenced in an allosteric manner by surrounding residues, like those of the extracellular loops (ECLs) that form the vestibule. Exploiting these allosteric influences may facilitate the development of more subtype-selective ligands for GPCRs.

Constrained catecholamines gain beta(2)AR selectivity through allosteric effects on pocket dynamics.,Xu X, Shonberg J, Kaindl J, Clark MJ, Stossel A, Maul L, Mayer D, Hubner H, Hirata K, Venkatakrishnan AJ, Dror RO, Kobilka BK, Sunahara RK, Liu X, Gmeiner P Nat Commun. 2023 Apr 14;14(1):2138. doi: 10.1038/s41467-023-37808-y. PMID:37059717<ref>PMID:37059717</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7xka" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Escherichia virus T4]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Clark M]]
[[Category: Dror R]]
[[Category: Gmeiner P]]
[[Category: Hubner H]]
[[Category: Kaindl J]]
[[Category: Kobilka BK]]
[[Category: Liu X]]
[[Category: Maul L]]
[[Category: Mayer D]]
[[Category: Shonberg J]]
[[Category: Stobel A]]
[[Category: Sunahara R]]
[[Category: Venkatakrishnan A]]
[[Category: Xu X]]