View source for 9f33


==Cryo-EM structure of Dopamine 3 Receptor:Go complex bound to bitopic FOB02-04A - Conformation A==
<StructureSection load='9f33' size='340' side='right'caption='[[9f33]], [[Resolution|resolution]] 3.05&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9f33]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Aequorea_victoria Aequorea victoria], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens], [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus] and [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9F33 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9F33 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.05&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1H9N:~{N}-[2-[(1~{R},2~{S})-2-[[(2~{S},5~{S})-2-(6-azanylpyridin-3-yl)-5-methyl-morpholin-4-yl]methyl]cyclopropyl]ethyl]-1~{H}-indole-2-carboxamide'>A1H9N</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=9f33 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9f33 OCA], [https://pdbe.org/9f33 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9f33 RCSB], [https://www.ebi.ac.uk/pdbsum/9f33 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9f33 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/GBG2_HUMAN GBG2_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity).
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== Publication Abstract from PubMed ==
Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity and improve current medications by reducing off-target side effects. However, the lack of structural information on their binding mode impedes rational design. Here we determine the cryo-EM structure of the hD(3)R:Galpha(O)betagamma complex bound to the D(3)R selective bitopic agonist FOB02-04A. Structural, functional and computational analyses provide insights into its binding mode and point to a new TM2-ECL1-TM1 region, which requires the N-terminal ordering of TM1, as a major determinant of subtype selectivity in aminergic GPCRs. This region is underexploited in drug development, expands the established secondary binding pocket in aminergic GPCRs and could potentially be used to design novel and subtype selective drugs.

A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site.,Arroyo-Urea S, Nazarova AL, Carrion-Antoli A, Bonifazi A, Battiti FO, Lam JH, Newman AH, Katritch V, Garcia-Nafria J Nat Commun. 2024 Sep 5;15(1):7759. doi: 10.1038/s41467-024-51993-4. PMID:39237617<ref>PMID:39237617</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
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</StructureSection>
[[Category: Aequorea victoria]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Rattus norvegicus]]
[[Category: Arroyo-Urea S]]
[[Category: Garcia-Nafria J]]