7K65

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

Summary for 7K65

• Entry DOI: 10.2210/pdb7k65/pdb
• EMDB information: 22689
• Descriptor: Protein patched homolog 1, nanobody TI23, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: membrane protein
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 2
• Total formula weight: 162633.06

Authors

Zhang, Y.,Bulkley, D.P.,Liang, J.,Manglik, A.,Cheng, Y.,Beachy, P.A. (deposition date: 2020-09-18, release date: 2021-03-17)

Primary citation

Zhang, Y.,Lu, W.J.,Bulkley, D.P.,Liang, J.,Ralko, A.,Han, S.,Roberts, K.J.,Li, A.,Cho, W.,Cheng, Y.,Manglik, A.,Beachy, P.A.
Hedgehog pathway activation through nanobody-mediated conformational blockade of the Patched sterol conduit.
Proc.Natl.Acad.Sci.USA, 117:28838-28846, 2020

PubMed Abstract: 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.

PubMed: 33139559
DOI: 10.1073/pnas.2011560117

Experimental method

ELECTRON MICROSCOPY (3.4 Å)