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Hedgehog pathway activation through conformational blockade of the Patched sterol conduit

By Yunxiao Zhang, Wan-Jin Lu, David P Bulkley, Jiahao Liang, Arthur Ralko, Kelsey J Roberts, Anping Li, Wonhwa Cho, Yifan Cheng, Aashish Manglik, Philip A. Beachy

Posted 26 Sep 2019
bioRxiv DOI: 10.1101/783290

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 therapeutic application has been difficult for lack of agents amenable to tissue targeting. We have developed a novel agonist, a conformation-specific nanobody against the Hedgehog receptor Patched1. 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 cryo-EM structure determination. Although this conformation likely constitutes part of the transport cycle, nanobody-trapping disrupts the cycle and prevents substrate movement through the Patched1 sterol conduit. Our conformation-selective nanobody approach provides a new route to the development of transporter-related pharmacologic agents and may be generally applicable to the study of other transporters.

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