8w1v: Difference between revisions

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-'''Unreleased structure'''
-The entry 8w1v is ON HOLD  until Paper Publication
+==The beta2 adrenergic receptor bound to a bitopic ligand==
+<StructureSection load='8w1v' size='340' side='right'caption='[[8w1v]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8w1v]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8W1V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8W1V 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&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1AE2:(2S)-1-[(3-{1-[4-(4-{(2S)-2-hydroxy-3-[(propan-2-yl)amino]propoxy}phenyl)butyl]-1H-1,2,3-triazol-4-yl}propyl)amino]-3-(2-propylphenoxy)propan-2-ol'>A1AE2</scene>, <scene name='pdbligand=AV0:Lauryl+Maltose+Neopentyl+Glycol'>AV0</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=8w1v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8w1v OCA], [https://pdbe.org/8w1v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8w1v RCSB], [https://www.ebi.ac.uk/pdbsum/8w1v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8w1v 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 ==
+Metastable binding sites (MBS) have been observed in a multitude of molecular dynamics simulations and can be considered low affinity allosteric binding sites (ABS) that function as stepping stones as the ligand moves toward the orthosteric binding site (OBS). Herein, we show that MBS can be utilized as ABS in ligand design, resulting in ligands with improved binding kinetics. Four homobivalent bitopic ligands (1-4) were designed by molecular docking of (S)-alprenolol ((S)-ALP) in the cocrystal structure of the beta(2) adrenergic receptor (beta(2)AR) bound to the antagonist ALP. Ligand 4 displayed a potency and affinity similar to (S)-ALP, but with a &gt;4-fold increase in residence time. The proposed binding mode was confirmed by X-ray crystallography of ligand 4 in complex with the beta(2)AR. This ligand design principle can find applications beyond the beta(2)AR and G protein-coupled receptors (GPCRs) as a general approach for improving the pharmacological profile of orthosteric ligands by targeting the OBS and an MBS simultaneously.
-Authors: Gaiser, B., Danielsen, M., Xu, X., Jorgensen, K., Fronik, P., Marcher-Rorsted, E., Wrobe, T., Hirata, K., Liu, X., Mathiesen, J., Pedersen, D.
+Bitopic Ligands Support the Presence of a Metastable Binding Site at the beta(2) Adrenergic Receptor.,Gaiser BI, Danielsen M, Xu X, Ropke Jorgensen K, Fronik P, Marcher-Rorsted E, Wrobel TM, Liu X, Mosolff Mathiesen J, Sejer Pedersen D J Med Chem. 2024 Jul 11;67(13):11053-11068. doi: 10.1021/acs.jmedchem.4c00578. , Epub 2024 Jul 1. PMID:38952152<ref>PMID:38952152</ref>
-Description: The beta2 adrenergic receptor bound to a bitopic ligand
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Xu, X]]
+<div class="pdbe-citations 8w1v" style="background-color:#fffaf0;"></div>
-[[Category: Wrobe, T]]
+== References ==
-[[Category: Jorgensen, K]]
+<references/>
-[[Category: Liu, X]]
+__TOC__
-[[Category: Hirata, K]]
+</StructureSection>
-[[Category: Marcher-Rorsted, E]]
+[[Category: Homo sapiens]]
-[[Category: Mathiesen, J]]
+[[Category: Lama glama]]
-[[Category: Pedersen, D]]
+[[Category: Large Structures]]
-[[Category: Danielsen, M]]
+[[Category: Danielsen M]]
-[[Category: Fronik, P]]
+[[Category: Fronik P]]
-[[Category: Gaiser, B]]
+[[Category: Gaiser B]]
+[[Category: Hirata K]]
+[[Category: Jorgensen K]]
+[[Category: Liu X]]
+[[Category: Marcher-Rorsted E]]
+[[Category: Mathiesen J]]
+[[Category: Pedersen D]]
+[[Category: Wrobe T]]
+[[Category: Xu X]]