Structure, mechanism, and inhibition of Hedgehog acyltransferase.
Structure, mechanism, and inhibition of Hedgehog acyltransferase.
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刺猬酰基转移酶的结构、机制及抑制作用。
DOI：
10.1016/j.molcel.2021.11.018
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发表时间：
2021-12-16
期刊：
影响因子：
16
通讯作者：
Siebold C
中科院分区：
文献类型：
--
作者：
Coupland CE;Andrei SA;Ansell TB;Carrique L;Kumar P;Sefer L;Schwab RA;Byrne EFX;Pardon E;Steyaert J;Magee AI;Lanyon-Hogg T;Sansom MSP;Tate EW;Siebold C
Sonic Hedgehog（SHH）形态发生通路是胚胎发育和干细胞维持的基础，并与各种癌症有关。信号传导中的关键步骤是棕榈酸酯基团转移到SHH N末端，由多通道跨膜酶Hedgehog酰基转移酶（HHAT）催化。我们提出了HHAT结合底物类似物棕榈酰辅酶A和SHH模拟megabody的高分辨率cryo-EM结构，揭示了HHAT功能所必需的HHAT结合血红素基团。HHAT结合到有效的小分子抑制剂IMP-1575的结构揭示了封闭底物结合的活性位点的构象变化。我们的多学科分析提供了一个详细的机制，HHAT适应膜环境转移跨内质网膜的酰基链。膜结合O-酰基转移酶（MBOAT）超家族成员的这种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。HHAT与SHH模拟大二聚体复合物的高分辨率冷冻电镜结构血红素在膜腔中与HHAT Cys 324结合，并且对于功能是必需的棕榈辅酶A在邻近催化组氨酸的中心HHAT腔中结合。竞争性抑制剂IMP-1575引起活性位点的构象变化HHAT是Hedgehog信号传导途径中的关键酶，并且是膜结合O-半胱氨酸的蛋白质底物成员。酰基转移酶（MBOAT）超家族。Coupland等人报道了HHAT与酰基供体底物、megabody和抑制剂IMP-1575结合的cryo-EM结构，提供了对HHAT的结构-功能关系、机制和抑制基础的深入了解。
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. High-resolution cryo-EM structure of HHAT in complex with a SHH-mimetic megabody Heme is bound to HHAT Cys324 in a membrane cavity and is essential for function Palm-CoA binds in a central HHAT cavity adjacent to the catalytic histidine The competitive inhibitor IMP-1575 causes conformational changes in the active site HHAT is a key enzyme in the Hedgehog signaling pathway and protein-substrate member of the membrane-bound O-acyltransferase (MBOAT) superfamily. Coupland et al. report the cryo-EM structures of HHAT bound to acyl-donor substrate, megabody, and inhibitor IMP-1575, providing insight into the structure-function relationship of HHAT, mechanism, and the basis for inhibition.
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影响因子：
3.7
作者：
Buglino JA;Resh MD
通讯作者：
Resh MD
外部测序确定了涉及智力残疾的三个新型候选基因。
影响因子：
3.7
作者：
Agha Z;Iqbal Z;Azam M;Ayub H;Vissers LE;Gilissen C;Ali SH;Riaz M;Veltman JA;Pfundt R;van Bokhoven H;Qamar R
通讯作者：
Qamar R
影响因子：
4.5
作者：
Callier P;Calvel P;Matevossian A;Makrythanasis P;Bernard P;Kurosaka H;Vannier A;Thauvin-Robinet C;Borel C;Mazaud-Guittot S;Rolland A;Desdoits-Lethimonier C;Guipponi M;Zimmermann C;Stévant I;Kuhne F;Conne B;Santoni F;Lambert S;Huet F;Mugneret F;Jaruzelska J;Faivre L;Wilhelm D;Jégou B;Trainor PA;Resh MD;Antonarakis SE;Nef S
通讯作者：
Nef S
影响因子：
5.5
作者：
de Jong, Djurre H.;Singh, Gurpreet;Marrink, Siewert J.
通讯作者：
Marrink, Siewert J.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH