4JKV

Structure of the human smoothened 7TM receptor in complex with an antitumor agent

Summary for 4JKV

• Entry DOI: 10.2210/pdb4jkv/pdb
• Descriptor: Soluble cytochrome b562, Smoothened homolog, 4-fluoro-N-methyl-N-{1-[4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl]piperidin-4-yl}-2-(trifluoromethyl)benzamide, (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate, ... (8 entities in total)
• Functional Keywords: human smoothened receptor, antitumor agent, novel protein engineering, gpcr network, membrane protein, psi-biology, structural genomics, gpcr, membrane
• Biological source: Escherichia coli (human); More
• Cellular location: Membrane ; Multi-pass membrane protein : Q99835
• Total number of polymer chains: 2
• Total formula weight: 110453.73

Authors

Wang, C.,Wu, H.,Katritch, V.,Han, G.W.,Huang, X.,Liu, W.,Siu, F.Y.,Roth, B.L.,Cherezov, V.,Stevens, R.C.,GPCR Network (GPCR) (deposition date: 2013-03-11, release date: 2013-04-24, Last modification date: 2024-11-06)

Primary citation

Wang, C.,Wu, H.,Katritch, V.,Han, G.W.,Huang, X.P.,Liu, W.,Siu, F.Y.,Roth, B.L.,Cherezov, V.,Stevens, R.C.
Structure of the human smoothened receptor bound to an antitumour agent.
Nature, 497:338-343, 2013

PubMed Abstract: The smoothened (SMO) receptor, a key signal transducer in the hedgehog signalling pathway, is responsible for the maintenance of normal embryonic development and is implicated in carcinogenesis. It is classified as a class frizzled (class F) G-protein-coupled receptor (GPCR), although the canonical hedgehog signalling pathway involves the GLI transcription factors and the sequence similarity with class A GPCRs is less than 10%. Here we report the crystal structure of the transmembrane domain of the human SMO receptor bound to the small-molecule antagonist LY2940680 at 2.5 Å resolution. Although the SMO receptor shares the seven-transmembrane helical fold, most of the conserved motifs for class A GPCRs are absent, and the structure reveals an unusually complex arrangement of long extracellular loops stabilized by four disulphide bonds. The ligand binds at the extracellular end of the seven-transmembrane-helix bundle and forms extensive contacts with the loops.

PubMed: 23636324
DOI: 10.1038/nature12167

Experimental method

X-RAY DIFFRACTION (2.45 Å)