title: Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs.
abstract: The Smoothened receptor (SMO) mediates signal transduction in the hedgehog pathway, which is implicated in normal development and carcinogenesis. SMO antagonists can suppress the growth of some tumours; however, mutations at SMO have been found to abolish their antitumour effects, a phenomenon known as chemoresistance. Here we report three crystal structures of human SMO bound to the antagonists SANT1 and Anta XV, and the agonist, SAG1.5, at 2.6-2.8 Å resolution. The long and narrow cavity in the transmembrane domain of SMO harbours multiple ligand binding sites, where SANT1 binds at a deeper site as compared with other ligands. Distinct interactions at D473(6.54f) elucidated the structural basis for the differential effects of chemoresistance mutations on SMO antagonists. The agonist SAG1.5 induces a conformational rearrangement of the binding pocket residues, which could contribute to SMO activation. Collectively, these studies reveal the structural basis for the modulation of SMO by small molecules.
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Chong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Huixian
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Tama
authors.initials: T
authors.lastname: Evron
authors.affiliation: Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, 4072 Genetic Medicine Building, Chapel Hill, North Carolina 27514, USA.
authors.forename: Eyal
authors.initials: E
authors.lastname: Vardy
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Gye Won
authors.initials: GW
authors.lastname: Han
authors.affiliation: Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, 4072 Genetic Medicine Building, Chapel Hill, North Carolina 27514, USA.
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.affiliation: Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, 4072 Genetic Medicine Building, Chapel Hill, North Carolina 27514, USA.
authors.forename: Sandy J
authors.initials: SJ
authors.lastname: Hufeisen
authors.affiliation: Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, 4072 Genetic Medicine Building, Chapel Hill, North Carolina 27514, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Mangano
authors.affiliation: Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, 4072 Genetic Medicine Building, Chapel Hill, North Carolina 27514, USA.
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Urban
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Katritch
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Vadim
authors.initials: V
authors.lastname: Cherezov
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
authors.affiliation: Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, 4072 Genetic Medicine Building, Chapel Hill, North Carolina 27514, USA.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D003461:Crystallography; D003514:Cyclohexylamines / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D053823:Hedgehog Proteins / Q000502:physiology; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008958:Models, Molecular; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D000072086:Smoothened Receptor; D013876:Thiophenes / Q000494:pharmacology
chemical_list: C097388:2-N,N-bis(carboxymethyl)lysine; C000621105:Anta XV; D000970:Antineoplastic Agents; D003514:Cyclohexylamines; D053823:Hedgehog Proteins; D010793:Phthalazines; D010879:Piperazines; D011720:Pyrazoles; D043562:Receptors, G-Protein-Coupled; C468918:SAG compound; C468919:SANT-1 compound; C491023:SMO protein, human; D000072086:Smoothened Receptor; D013876:Thiophenes; D008239:Lysine