5V56

2.9A XFEL structure of the multi-domain human smoothened receptor (with E194M mutation) in complex with TC114

5V56 の概要

• エントリーDOI: 10.2210/pdb5v56/pdb
• 関連するPDBエントリー: 5V57
• 分子名称: Smoothened homolog,Flavodoxin,Smoothened homolog, N-methyl-N-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-yl]-4-nitro-2-(trifluoromethyl)benzamide, FLAVIN MONONUCLEOTIDE, ... (4 entities in total)
• 機能のキーワード: human smoothened receptor complex, gpcr hedgehog signaling, gpcr, class f, 7tm domain, hinge domain, extracellular cystein-rich domain, flavodoxin, membrane protein, lcp, xfel, tc114
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 147366.09

構造登録者

Zhang, X.,Zhao, F.,Wu, Y.,Yang, J.,Han, G.W.,Zhao, S.,Ishchenko, A.,Ye, L.,Lin, X.,Ding, K.,Dharmarajan, V.,Griffin, P.R.,Gati, C.,Nelson, G.,Hunter, M.S.,Hanson, M.A.,Cherezov, V.,Stevens, R.C.,Tan, W.,Tao, H.,Xu, F. (登録日: 2017-03-13, 公開日: 2017-05-24, 最終更新日: 2023-11-08)

主引用文献

Zhang, X.,Zhao, F.,Wu, Y.,Yang, J.,Han, G.W.,Zhao, S.,Ishchenko, A.,Ye, L.,Lin, X.,Ding, K.,Dharmarajan, V.,Griffin, P.R.,Gati, C.,Nelson, G.,Hunter, M.S.,Hanson, M.A.,Cherezov, V.,Stevens, R.C.,Tan, W.,Tao, H.,Xu, F.
Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand.
Nat Commun, 8:15383-15383, 2017

PubMed Abstract: The Smoothened receptor (SMO) belongs to the Class Frizzled of the G protein-coupled receptor (GPCR) superfamily, constituting a key component of the Hedgehog signalling pathway. Here we report the crystal structure of the multi-domain human SMO, bound and stabilized by a designed tool ligand TC114, using an X-ray free-electron laser source at 2.9 Å. The structure reveals a precise arrangement of three distinct domains: a seven-transmembrane helices domain (TMD), a hinge domain (HD) and an intact extracellular cysteine-rich domain (CRD). This architecture enables allosteric interactions between the domains that are important for ligand recognition and receptor activation. By combining the structural data, molecular dynamics simulation, and hydrogen-deuterium-exchange analysis, we demonstrate that transmembrane helix VI, extracellular loop 3 and the HD play a central role in transmitting the signal employing a unique GPCR activation mechanism, distinct from other multi-domain GPCRs.

PubMed: 28513578
DOI: 10.1038/ncomms15383

実験手法

X-RAY DIFFRACTION (2.9 Å)