Structure and dynamics of the essential endogenous mycobacterial polyketide synthase Pks13.
Structure and dynamics of the essential endogenous mycobacterial polyketide synthase Pks13.
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DOI：
10.1038/s41594-022-00918-0
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发表时间：
2023-03
影响因子：
16.8
通讯作者：
Stroud, Robert M.
中科院分区：
文献类型：
--
作者：
Kim, Sun Kyung;Dickinson, Miles Sasha;Finer-Moore, Janet;Guan, Ziqiang;Kaake, Robyn M.;Echeverria, Ignacia;Chen, Jen;Pulido, Ernst H.;Sali, Andrej;Krogan, Nevan J.;Rosenberg, Oren S.;Stroud, Robert M.
结核分枝杆菌细胞壁的分枝菌酸层对于生存力和毒力是必不可少的，并且负责其合成的酶是抗分枝杆菌药物开发的靶点。聚酮合酶13（Pks 13）是编码几种酶和转运功能的模块，其进行两种不同长链脂肪酸的缩合以产生分枝菌酸。我们确定的结构，通过低温电子显微镜的二聚体多酶Pks 13纯化的分枝杆菌在正常生长条件下，捕获与本地基板。结构定义了酮合酶（KS）、接头和酰基转移酶（AT）结构域（分辨率为1.8 nm）和N-末端酰基载体蛋白（ACP 1）的两个交替位置。这些结构表明中间状态的途径底物交付的酮合酶结构域。在较低分辨率下可见的其他域相对于KS-AT核心是灵活的。通过电喷雾电离质谱法确定了三种结合的内源性长链脂肪酸底物的化学结构。来自分枝杆菌的聚酮合酶13是内源性纯化的，与野生型底物结合。cryoEM的结构通过关键药物靶标在分枝菌酸合成的最后一步中定义了酰基载体蛋白的多种状态。
The mycolic acid layer of the Mycobacterium tuberculosis cell wall is essential for viability and virulence, and the enzymes responsible for its synthesis are targets for antimycobacterial drug development. Polyketide synthase 13 (Pks13) is a module encoding several enzymatic and transport functions that carries out the condensation of two different long-chain fatty acids to produce mycolic acids. We determined structures by cryogenic electron microscopy of dimeric multi-enzyme Pks13 purified from mycobacteria under normal growth conditions, captured with native substrates. Structures define the ketosynthase (KS), linker, and acyltransferase (AT) domains at 1.8 Å resolution and two alternate locations of the N-terminal acyl carrier protein (ACP1). These structures suggest intermediate states on the pathway for substrate delivery to the ketosynthase domain. Other domains, visible at lower resolution, are flexible relative to the KS-AT core. The chemical structures of three bound endogenous long-chain fatty acid substrates were determined by electrospray ionization mass spectrometry. Polyketide synthase 13 from mycobacteria, was purified endogenously ‘in action’, with wild type substrates bound. Structures by cryoEM define multiple states of acyl carrier proteins in the final step of mycolic acid synthesis, by a key drug target.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
14.8
作者：
Kelley LA;Mezulis S;Yates CM;Wass MN;Sternberg MJ
通讯作者：
Sternberg MJ
影响因子：
5.7
作者：
Keatinge-Clay, AT;Shelat, AA;Stroud, RM
通讯作者：
Stroud, RM
DOI：
10.1107/s2059798318006551
发表时间：
2018-06-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Poon BK;Read RJ;Sobolev OV;Terwilliger TC;Urzhumtsev A;Adams PD
通讯作者：
Adams PD
影响因子：
14.8
作者：
Grzegorzewicz, Anna E.;Ha Pham;Gundi, Vijay A. K. B.;Scherman, Michael S.;North, Elton J.;Hess, Tamara;Jones, Victoria;Gruppo, Veronica;Born, Sarah E. M.;Kordulakova, Jana;Chavadi, Sivagami Sundaram;Morisseau, Christophe;Lenaerts, Anne J.;Lee, Richard E.;McNeil, Michael R.;Jackson, Mary
通讯作者：
Jackson, Mary