Structural basis for Smoothened receptor modulation and chemoresistance to anti-cancer drugs

By Chong Wang, Huixian Wu, Tama Evron, E. Vardy, G. Han, Xi-Ping Huang, S. Hufeisen, T. Mangano, D. Urban, Vsevolod Katritch and 4 more. 2014

258 citations recorded by the source corpus.

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. Antagonists of Smoothened, a class F GPCR involved in the hedgehog pathway, have been developed to treat some cancers. Here Wang et al.report structures of Smoothened in complex with antagonists and an agonist, and describe how mutations may result in resistance to anti-Smoothened treatment.

Subfields: Molecular Biology

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Citations in the corpus

GPCRdb in 2021: integrating GPCR sequence, structure and function (2020, methodology): “The generic residue numbering uses a structural investigation to confirm or correct the receptor residue that corresponds to the reference position (designated the number 50) in each of TM1–7 using the sequence-based numbering scheme for the given GPCR class (A: BallesterosWeinstein (13), B1: Wootte”
Integrating structural and mutagenesis data to elucidate GPCR ligand binding (2016, background): “Finally, the class F receptor, smoothened (SMO), has been crystallised with multiple ligands-the first [16] binding close to the extracellular surface, but others covering a great vertical span [17].”
A Structural Framework for GPCR Chemogenomics: What's In a Residue Number? (2018, methodology): “GPCR Classes Numbering schemes using a similar logic to the BW numbering have later been proposed by Wootten for class B [58], Pin for class C [59], and Wang for class F GPCRs [19].”