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Hedgehog 酰基转移酶的结构、机制和抑制作用。

Structure, mechanism, and inhibition of Hedgehog acyltransferase.

机构信息

Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.

Department of Chemistry, Imperial College London, 82 Wood Lane, London W12 0BZ, UK.

出版信息

Mol Cell. 2021 Dec 16;81(24):5025-5038.e10. doi: 10.1016/j.molcel.2021.11.018. Epub 2021 Dec 9.

DOI:10.1016/j.molcel.2021.11.018
PMID:34890564
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8693861/
Abstract

The Sonic Hedgehog (SHH) morphogen pathway is fundamental for embryonic development and stem cell maintenance and is implicated in various cancers. A key step in signaling is transfer of a palmitate group to the SHH N terminus, catalyzed by the multi-pass transmembrane enzyme Hedgehog acyltransferase (HHAT). We present the high-resolution cryo-EM structure of HHAT bound to substrate analog palmityl-coenzyme A and a SHH-mimetic megabody, revealing a heme group bound to HHAT that is essential for HHAT function. A structure of HHAT bound to potent small-molecule inhibitor IMP-1575 revealed conformational changes in the active site that occlude substrate binding. Our multidisciplinary analysis provides a detailed view of the mechanism by which HHAT adapts the membrane environment to transfer an acyl chain across the endoplasmic reticulum membrane. This structure of a membrane-bound O-acyltransferase (MBOAT) superfamily member provides a blueprint for other protein-substrate MBOATs and a template for future drug discovery.

摘要

Sonic Hedgehog (SHH) 形态发生素途径对胚胎发育和干细胞维持至关重要，并与各种癌症有关。信号转导的关键步骤是将棕榈酸基团转移到 SHH N 端，由多跨膜酶 Hedgehog 酰基转移酶 (HHAT) 催化。我们展示了与底物类似物棕榈酰辅酶 A 和 SHH 模拟巨肽结合的 HHAT 的高分辨率冷冻电镜结构，揭示了结合到 HHAT 的血红素基团对 HHAT 功能至关重要。与有效小分子抑制剂 IMP-1575 结合的 HHAT 的结构显示了活性位点的构象变化，从而阻止了底物结合。我们的多学科分析提供了 HHAT 如何适应膜环境将酰基链穿过内质网膜的详细机制。这种膜结合 O-酰基转移酶 (MBOAT) 超家族成员的结构为其他蛋白质-底物 MBOAT 提供了蓝图，并为未来的药物发现提供了模板。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a9d/8693861/c69c10a76596/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a9d/8693861/e1b200b3d9f5/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a9d/8693861/e23d556657cf/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a9d/8693861/1c63c856742a/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a9d/8693861/6c1dd90b8eb7/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a9d/8693861/84d03f939e52/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a9d/8693861/1f99274e5717/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a9d/8693861/273da5e9d1dc/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a9d/8693861/c69c10a76596/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a9d/8693861/e1b200b3d9f5/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a9d/8693861/e23d556657cf/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a9d/8693861/1c63c856742a/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a9d/8693861/6c1dd90b8eb7/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a9d/8693861/84d03f939e52/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a9d/8693861/1f99274e5717/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a9d/8693861/273da5e9d1dc/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7a9d/8693861/c69c10a76596/gr7.jpg

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