+検索条件
-Structure paper
タイトル | Hedgehog pathway activation through nanobody-mediated conformational blockade of the Patched sterol conduit. |
---|---|
ジャーナル・号・ページ | Proc Natl Acad Sci U S A, Vol. 117, Issue 46, Page 28838-28846, Year 2020 |
掲載日 | 2020年11月17日 |
著者 | Yunxiao Zhang / Wan-Jin Lu / David P Bulkley / Jiahao Liang / Arthur Ralko / Shuo Han / Kelsey J Roberts / Anping Li / Wonhwa Cho / Yifan Cheng / Aashish Manglik / Philip A Beachy / |
PubMed 要旨 | 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, ...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. |
リンク | Proc Natl Acad Sci U S A / PubMed:33139559 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.4 Å |
構造データ | EMDB-22689, PDB-7k65: |
化合物 | ChemComp-NAG: ChemComp-Q7G: |
由来 |
|
キーワード | MEMBRANE PROTEIN |