title: Structural insights into the role of the Smoothened cysteine-rich domain in Hedgehog signalling.
abstract: Smoothened (Smo) is a member of the Frizzled (FzD) class of G-protein-coupled receptors (GPCRs), and functions as the key transducer in the Hedgehog (Hh) signalling pathway. Smo has an extracellular cysteine-rich domain (CRD), indispensable for its function and downstream Hh signalling. Despite its essential role, the functional contribution of the CRD to Smo signalling has not been clearly elucidated. However, given that the FzD CRD binds to the endogenous Wnt ligand, it has been proposed that the Smo CRD may bind its own endogenous ligand. Here we present the NMR solution structure of the Drosophila Smo CRD, and describe interactions between the glucocorticoid budesonide (Bud) and the Smo CRDs from both Drosophila and human. Our results highlight a function of the Smo CRD, demonstrating its role in binding to small-molecule modulators.
authors.affiliation: 1] Department of Structural Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2] Integrated Program in Biomedical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38105, USA.
authors.forename: Rajashree
authors.initials: R
authors.lastname: Rana
authors.affiliation: 1] Department of Biochemistry, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2].
authors.forename: Candace E
authors.initials: CE
authors.lastname: Carroll
authors.affiliation: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Ho-Jin
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Ju
authors.initials: J
authors.lastname: Bao
authors.affiliation: Department of Biochemistry, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Marada
authors.affiliation: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Christy R R
authors.initials: CR
authors.lastname: Grace
authors.affiliation: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Cristina D
authors.initials: CD
authors.lastname: Guibao
authors.affiliation: 1] Integrated Program in Biomedical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38105, USA [2] Department of Biochemistry, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Stacey K
authors.initials: SK
authors.lastname: Ogden
authors.affiliation: 1] Department of Structural Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2] Integrated Program in Biomedical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38105, USA.
authors.forename: Jie J
authors.initials: JJ
authors.lastname: Zheng
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019819:Budesonide / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster; D051157:Frizzled Receptors / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D000072086:Smoothened Receptor; D013045:Species Specificity
chemical_list: D029721:Drosophila Proteins; D051157:Frizzled Receptors; D005938:Glucocorticoids; D053823:Hedgehog Proteins; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; C100664:smo protein, Drosophila; D019819:Budesonide