7k65

Hedgehog receptor Patched (PTCH1) in complex with conformation selective nanobody TI23

spinqualitylabelsall models 7k65, resolution 3.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7k65 is a 2 chain structure with sequence from Lama glama and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.4Å Ligands: NAG, Q7G Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PTC1_MOUSE Acts as a receptor for sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH). Associates with the smoothened protein (SMO) to transduce the hedgehog's proteins signal. Seems to have a tumor suppressor function, as inactivation of this protein is probably a necessary, if not sufficient step for tumorigenesis. Publication Abstract from PubMed Activation of the Hedgehog pathway may have therapeutic value for improved bone healing, taste receptor cell regeneration, and alleviation of colitis or other conditions. Systemic pathway activation, however, may be detrimental, and agents amenable to tissue targeting for therapeutic application have been lacking. We have developed an agonist, a conformation-specific nanobody against the Hedgehog receptor Patched1 (PTCH1). This nanobody potently activates the Hedgehog pathway in vitro and in vivo by stabilizing an alternative conformation of a Patched1 "switch helix," as revealed by our cryogenic electron microscopy structure. Nanobody-binding likely traps Patched in one stage of its transport cycle, thus preventing substrate movement through the Patched1 sterol conduit. Unlike the native Hedgehog ligand, this nanobody does not require lipid modifications for its activity, facilitating mechanistic studies of Hedgehog pathway activation and the engineering of pathway activating agents for therapeutic use. Our conformation-selective nanobody approach may be generally applicable to the study of other PTCH1 homologs. Hedgehog pathway activation through nanobody-mediated conformational blockade of the Patched sterol conduit.,Zhang Y, Lu WJ, Bulkley DP, Liang J, Ralko A, Han S, Roberts KJ, Li A, Cho W, Cheng Y, Manglik A, Beachy PA Proc Natl Acad Sci U S A. 2020 Nov 2. pii: 2011560117. doi:, 10.1073/pnas.2011560117. PMID:33139559 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Protein patched homolog 1

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