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==Crystal structure of the neurotensin receptor 1 in complex with the small-molecule partial agonist RTI-3a== | ==Crystal structure of the neurotensin receptor 1 in complex with the small-molecule partial agonist RTI-3a== | ||
<StructureSection load='6za8' size='340' side='right'caption='[[6za8]]' scene=''> | <StructureSection load='6za8' size='340' side='right'caption='[[6za8]], [[Resolution|resolution]] 2.72Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZA8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZA8 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6za8]] is a 1 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=6ZA8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZA8 FirstGlance]. <br> | ||
</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=6za8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6za8 OCA], [https://pdbe.org/6za8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6za8 RCSB], [https://www.ebi.ac.uk/pdbsum/6za8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6za8 ProSAT]</span></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]] 2.72Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SR5:(2~{S})-2-[[1-(7-chloranylquinolin-4-yl)-5-(2,6-dimethoxyphenyl)pyrazol-3-yl]carbonylamino]-4-methyl-pentanoic+acid'>SR5</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=6za8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6za8 OCA], [https://pdbe.org/6za8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6za8 RCSB], [https://www.ebi.ac.uk/pdbsum/6za8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6za8 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/NTR1_RAT NTR1_RAT] Receptor for the tridecapeptide neurotensin. It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Neurotensin receptor 1 (NTSR1) and related G protein-coupled receptors of the ghrelin family are clinically unexploited, and several mechanistic aspects of their activation and inactivation have remained unclear. Enabled by a new crystallization design, we present five new structures: apo-state NTSR1 as well as complexes with nonpeptide inverse agonists SR48692 and SR142948A, partial agonist RTI-3a, and the novel full agonist SRI-9829, providing structural rationales on how ligands modulate NTSR1. The inverse agonists favor a large extracellular opening of helices VI and VII, undescribed so far for NTSR1, causing a constriction of the intracellular portion. In contrast, the full and partial agonists induce a binding site contraction, and their efficacy correlates with the ability to mimic the binding mode of the endogenous agonist neurotensin. Providing evidence of helical and side-chain rearrangements modulating receptor activation, our structural and functional data expand the mechanistic understanding of NTSR1 and potentially other peptidergic receptors. | |||
Complexes of the neurotensin receptor 1 with small-molecule ligands reveal structural determinants of full, partial, and inverse agonism.,Deluigi M, Klipp A, Klenk C, Merklinger L, Eberle SA, Morstein L, Heine P, Mittl PRE, Ernst P, Kamenecka TM, He Y, Vacca S, Egloff P, Honegger A, Pluckthun A Sci Adv. 2021 Jan 27;7(5):eabe5504. doi: 10.1126/sciadv.abe5504. Print 2021 Jan. PMID:33571132<ref>PMID:33571132</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6za8" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Neurotensin receptor|Neurotensin receptor]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Rattus norvegicus]] | |||
[[Category: Deluigi M]] | [[Category: Deluigi M]] | ||
[[Category: Hilge M]] | [[Category: Hilge M]] | ||
Revision as of 16:44, 24 January 2024
Crystal structure of the neurotensin receptor 1 in complex with the small-molecule partial agonist RTI-3aCrystal structure of the neurotensin receptor 1 in complex with the small-molecule partial agonist RTI-3a
Structural highlights
FunctionNTR1_RAT Receptor for the tridecapeptide neurotensin. It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. Publication Abstract from PubMedNeurotensin receptor 1 (NTSR1) and related G protein-coupled receptors of the ghrelin family are clinically unexploited, and several mechanistic aspects of their activation and inactivation have remained unclear. Enabled by a new crystallization design, we present five new structures: apo-state NTSR1 as well as complexes with nonpeptide inverse agonists SR48692 and SR142948A, partial agonist RTI-3a, and the novel full agonist SRI-9829, providing structural rationales on how ligands modulate NTSR1. The inverse agonists favor a large extracellular opening of helices VI and VII, undescribed so far for NTSR1, causing a constriction of the intracellular portion. In contrast, the full and partial agonists induce a binding site contraction, and their efficacy correlates with the ability to mimic the binding mode of the endogenous agonist neurotensin. Providing evidence of helical and side-chain rearrangements modulating receptor activation, our structural and functional data expand the mechanistic understanding of NTSR1 and potentially other peptidergic receptors. Complexes of the neurotensin receptor 1 with small-molecule ligands reveal structural determinants of full, partial, and inverse agonism.,Deluigi M, Klipp A, Klenk C, Merklinger L, Eberle SA, Morstein L, Heine P, Mittl PRE, Ernst P, Kamenecka TM, He Y, Vacca S, Egloff P, Honegger A, Pluckthun A Sci Adv. 2021 Jan 27;7(5):eabe5504. doi: 10.1126/sciadv.abe5504. Print 2021 Jan. PMID:33571132[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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