Structure, mechanism, and inhibition of Hedgehog acyltransferase

被引：39

作者：

Coupland, Claire E. ^{[1
]}

Andrei, Sebastian A. ^{[2
]}

Ansell, T. Bertie ^{[3
]}

Carrique, Loic ^{[1
]}

Kumar, Pramod ^{[1
]}

Sefer, Lea ^{[1
]}

Schwab, Rebekka A. ^{[1
]}

Byrne, Eamon F. X. ^{[1
,8
]}

Pardon, Els ^{[4
,5
]}

Steyaert, Jan ^{[4
,5
]}

Magee, Anthony, I ^{[6
]}

Lanyon-Hogg, Thomas ^{[7
]}

Sansom, Mark S. P. ^{[3
]}

Tate, Edward W. ^{[2
]}

Siebold, Christian ^{[1
]}

机构：

[1] Univ Oxford, Wellcome Ctr Human Genet, Div Struct Biol, Roosevelt Dr, Oxford OX3 7BN, England

[2] Imperial Coll London, Dept Chem, 82 Wood Lane, London W12 OBZ, England

[3] Univ Oxford, Dept Biochem, South Parks Rd, Oxford OX1 3QU, England

[4] Vrije Univ Brussel VUB, Struct Biol Brussels, Pl Laan 2, B-1050 Brussels, Belgium

[5] Vlaams Inst Biotechnol VIB, VIB VUB Ctr Struct Biol, Pl Laan 2, B-1050 Brussels, Belgium

[6] Imperial Coll London, Natl Heart & Lung Inst, Exhibit Rd, London SW7 2AZ, England

[7] Univ Oxford, Dept Pharmacol, Mansfield Rd, Oxford OX1 3QT, England

[8] Stanford Univ, Dept Bioengn, 443 Via Ortega, Stanford, CA 94305 USA

来源：

MOLECULAR CELL | 2021年 / 81卷 / 24期

基金：

英国生物技术与生命科学研究理事会;

关键词：

STRUCTURE VALIDATION; CRYO-EM; PALMITOYLATION; IDENTIFICATION; PROTEINS; VISUALIZATION; RECOGNITION; ALGORITHMS; GENERATION; REFINEMENT;

D O I：

10.1016/j.molcel.2021.11.018

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：5025 / +

页数：25

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