5V57

3.0A SYN structure of the multi-domain human smoothened receptor in complex with TC114

Summary for 5V57

• Entry DOI: 10.2210/pdb5v57/pdb
• Related: 5V56
• Descriptor: 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)
• Functional Keywords: human smoothened receptor complex, gpcr hedgehog signaling, gpcr, class f, 7tm domain, hinge domain, extracellular cystein-rich domain, flavodoxin, membrane protein, lcp, synchrotron radiation, tc114
• Biological source: Homo sapiens (Human); More
• Cellular location: Membrane ; Multi-pass membrane protein : Q99835
• Total number of polymer chains: 2
• Total formula weight: 146646.29

Authors

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. (deposition date: 2017-03-13, release date: 2017-05-24, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3 Å)