6ZFZ

Structure of M1-StaR-T4L in complex with 77-LH-28-1 at 2.17A

6ZFZ の概要

• エントリーDOI: 10.2210/pdb6zfz/pdb
• 分子名称: Muscarinic acetylcholine receptor M1,Endolysin,Muscarinic acetylcholine receptor M1, 1-[3-(4-butylpiperidin-1-yl)propyl]-3,4-dihydroquinolin-2-one, OLEIC ACID, ... (8 entities in total)
• 機能のキーワード: gpcr, 7tm, membrane protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 55411.76

構造登録者

Rucktooa, P.,Cooke, R.M. (登録日: 2020-06-18, 公開日: 2021-10-06, 最終更新日: 2024-11-13)

主引用文献

Brown, A.J.H.,Bradley, S.J.,Marshall, F.H.,Brown, G.A.,Bennett, K.A.,Brown, J.,Cansfield, J.E.,Cross, D.M.,de Graaf, C.,Hudson, B.D.,Dwomoh, L.,Dias, J.M.,Errey, J.C.,Hurrell, E.,Liptrot, J.,Mattedi, G.,Molloy, C.,Nathan, P.J.,Okrasa, K.,Osborne, G.,Patel, J.C.,Pickworth, M.,Robertson, N.,Shahabi, S.,Bundgaard, C.,Phillips, K.,Broad, L.M.,Goonawardena, A.V.,Morairty, S.R.,Browning, M.,Perini, F.,Dawson, G.R.,Deakin, J.F.W.,Smith, R.T.,Sexton, P.M.,Warneck, J.,Vinson, M.,Tasker, T.,Tehan, B.G.,Teobald, B.,Christopoulos, A.,Langmead, C.J.,Jazayeri, A.,Cooke, R.M.,Rucktooa, P.,Congreve, M.S.,Weir, M.,Tobin, A.B.
From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease.
Cell, 184:5886-, 2021

PubMed Abstract: 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.

PubMed: 34822784
DOI: 10.1016/j.cell.2021.11.001

実験手法

X-RAY DIFFRACTION (2.17 Å)