6zg9: Difference between revisions

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<StructureSection load='6zg9' size='340' side='right'caption='[[6zg9]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
<StructureSection load='6zg9' size='340' side='right'caption='[[6zg9]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6zg9]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZG9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZG9 FirstGlance]. <br>
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZG9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZG9 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=OLA:OLEIC+ACID'>OLA</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=QK2:7-fluoranyl-5-methyl-3-[1-(oxan-4-yl)piperidin-4-yl]-1~{H}-benzimidazol-2-one'>QK2</scene></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]] 2.5&#8491;</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Lysozyme Lysozyme], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.17 3.2.1.17] </span></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=OLA:OLEIC+ACID'>OLA</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=QK2:7-fluoranyl-5-methyl-3-[1-(oxan-4-yl)piperidin-4-yl]-1~{H}-benzimidazol-2-one'>QK2</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=6zg9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zg9 OCA], [https://pdbe.org/6zg9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zg9 RCSB], [https://www.ebi.ac.uk/pdbsum/6zg9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zg9 ProSAT]</span></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=6zg9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zg9 OCA], [https://pdbe.org/6zg9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zg9 RCSB], [https://www.ebi.ac.uk/pdbsum/6zg9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zg9 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
[[https://www.uniprot.org/uniprot/ACM1_HUMAN ACM1_HUMAN]] The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.
From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease.,Brown AJH, Bradley SJ, Marshall FH, Brown GA, Bennett KA, Brown J, Cansfield JE, Cross DM, de Graaf C, Hudson BD, Dwomoh L, Dias JM, Errey JC, Hurrell E, Liptrot J, Mattedi G, Molloy C, Nathan PJ, Okrasa K, Osborne G, Patel JC, Pickworth M, Robertson N, Shahabi S, Bundgaard C, Phillips K, Broad LM, Goonawardena AV, Morairty SR, Browning M, Perini F, Dawson GR, Deakin JFW, Smith RT, Sexton PM, Warneck J, Vinson M, Tasker T, Tehan BG, Teobald B, Christopoulos A, Langmead CJ, Jazayeri A, Cooke RM, Rucktooa P, Congreve MS, Weir M, Tobin AB Cell. 2021 Nov 24;184(24):5886-5901.e22. doi: 10.1016/j.cell.2021.11.001. PMID:34822784<ref>PMID:34822784</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6zg9" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Muscarinic acetylcholine receptor|Muscarinic acetylcholine receptor]]
*[[Muscarinic acetylcholine receptor|Muscarinic acetylcholine receptor]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Lysozyme]]
[[Category: Cooke RM]]
[[Category: Cooke, R M]]
[[Category: Rucktooa P]]
[[Category: Rucktooa, P]]
[[Category: Gpcr]]
[[Category: Membrane protein]]

Latest revision as of 13:47, 23 October 2024

Structure of M1-StaR-T4L in complex with GSK1034702 at 2.5AStructure of M1-StaR-T4L in complex with GSK1034702 at 2.5A

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.5Å
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

See Also

6zg9, resolution 2.50Å

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