Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs

Chong Wang, Huixian Wu, Tama Evron, Eyal Vardy, Gye Won Han, Xi-Ping Huang, Sandy J. Hufeisen, Thomas J. Mangano, Dan J. Urban, Vsevolod Katritch, Vadim Cherezov, Marc G. Caron, Bryan L. Roth and Raymond C. Stevens ()
Additional contact information
Chong Wang: The Scripps Research Institute
Huixian Wu: The Scripps Research Institute
Tama Evron: Duke University Medical Center
Eyal Vardy: National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School
Gye Won Han: The Scripps Research Institute
Xi-Ping Huang: National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School
Sandy J. Hufeisen: National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School
Thomas J. Mangano: National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School
Dan J. Urban: National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School
Vsevolod Katritch: The Scripps Research Institute
Vadim Cherezov: The Scripps Research Institute
Marc G. Caron: Duke University Medical Center
Bryan L. Roth: National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School
Raymond C. Stevens: The Scripps Research Institute

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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 D4736.54f 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.

Date: 2014
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DOI: 10.1038/ncomms5355

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