6ps1: Difference between revisions
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<StructureSection load='6ps1' size='340' side='right'caption='[[6ps1]], [[Resolution|resolution]] 3.20Å' scene=''> | <StructureSection load='6ps1' size='340' side='right'caption='[[6ps1]], [[Resolution|resolution]] 3.20Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6ps1]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PS1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PS1 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6ps1]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PS1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PS1 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=OLA:OLEIC+ACID'>OLA</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TIM:(2S)-1-(TERT-BUTYLAMINO)-3-[(4-MORPHOLIN-4-YL-1,2,5-THIADIAZOL-3-YL)OXY]PROPAN-2-OL'>TIM</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=OLA:OLEIC+ACID'>OLA</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TIM:(2S)-1-(TERT-BUTYLAMINO)-3-[(4-MORPHOLIN-4-YL-1,2,5-THIADIAZOL-3-YL)OXY]PROPAN-2-OL'>TIM</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADRB2, ADRB2R, B2AR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6ps1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ps1 OCA], [http://pdbe.org/6ps1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ps1 RCSB], [http://www.ebi.ac.uk/pdbsum/6ps1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ps1 ProSAT]</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=6ps1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ps1 OCA], [http://pdbe.org/6ps1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ps1 RCSB], [http://www.ebi.ac.uk/pdbsum/6ps1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ps1 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[[http://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. | [[http://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. | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Rational structure-based drug design (SBDD) relies on the availability of a large number of co-crystal structures to map the ligand-binding pocket of the target protein and use this information for lead-compound optimization via an iterative process. While SBDD has proven successful for many drug-discovery projects, its application to G protein-coupled receptors (GPCRs) has been limited owing to extreme difficulties with their crystallization. Here, a method is presented for the rapid determination of multiple co-crystal structures for a target GPCR in complex with various ligands, taking advantage of the serial femtosecond crystallography approach, which obviates the need for large crystals and requires only submilligram quantities of purified protein. The method was applied to the human beta2-adrenergic receptor, resulting in eight room-temperature co-crystal structures with six different ligands, including previously unreported structures with carvedilol and propranolol. The generality of the proposed method was tested with three other receptors. This approach has the potential to enable SBDD for GPCRs and other difficult-to-crystallize membrane proteins. | |||
Toward G protein-coupled receptor structure-based drug design using X-ray lasers.,Ishchenko A, Stauch B, Han GW, Batyuk A, Shiriaeva A, Li C, Zatsepin N, Weierstall U, Liu W, Nango E, Nakane T, Tanaka R, Tono K, Joti Y, Iwata S, Moraes I, Gati C, Cherezov V IUCrJ. 2019 Oct 24;6(Pt 6):1106-1119. doi: 10.1107/S2052252519013137. eCollection, 2019 Nov 1. PMID:31709066<ref>PMID:31709066</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6ps1" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Batyuk, A]] | [[Category: Batyuk, A]] | ||
Revision as of 16:07, 25 December 2019
XFEL beta2 AR structure by ligand exchange from Alprenolol to Timolol.XFEL beta2 AR structure by ligand exchange from Alprenolol to Timolol.
Structural highlights
Function[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. Publication Abstract from PubMedRational structure-based drug design (SBDD) relies on the availability of a large number of co-crystal structures to map the ligand-binding pocket of the target protein and use this information for lead-compound optimization via an iterative process. While SBDD has proven successful for many drug-discovery projects, its application to G protein-coupled receptors (GPCRs) has been limited owing to extreme difficulties with their crystallization. Here, a method is presented for the rapid determination of multiple co-crystal structures for a target GPCR in complex with various ligands, taking advantage of the serial femtosecond crystallography approach, which obviates the need for large crystals and requires only submilligram quantities of purified protein. The method was applied to the human beta2-adrenergic receptor, resulting in eight room-temperature co-crystal structures with six different ligands, including previously unreported structures with carvedilol and propranolol. The generality of the proposed method was tested with three other receptors. This approach has the potential to enable SBDD for GPCRs and other difficult-to-crystallize membrane proteins. Toward G protein-coupled receptor structure-based drug design using X-ray lasers.,Ishchenko A, Stauch B, Han GW, Batyuk A, Shiriaeva A, Li C, Zatsepin N, Weierstall U, Liu W, Nango E, Nakane T, Tanaka R, Tono K, Joti Y, Iwata S, Moraes I, Gati C, Cherezov V IUCrJ. 2019 Oct 24;6(Pt 6):1106-1119. doi: 10.1107/S2052252519013137. eCollection, 2019 Nov 1. PMID:31709066[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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