Structures of teixobactin-producing nonribosomal peptide synthetase condensation and adenylation domains

被引:14
|
作者
Tan, Kemin [1 ,2 ]
Zhou, Min [1 ,3 ]
Jedrzejczak, Robert P. [1 ,2 ]
Wu, Ruiying [1 ,2 ]
Higuera, Raul A. [4 ]
Borek, Dominika [5 ]
Babnigg, Gyorgy [1 ,3 ]
Joachimiak, Andrzej [1 ,2 ,6 ]
机构
[1] Univ Chicago, Ctr Struct Genom Infect Dis, 5735 South Ellis Ave, Chicago, IL 60637 USA
[2] Argonne Natl Lab, Xray Sci Div, Struct Biol Ctr, Adv Photon Source, 9700 S Cass Ave, Lemont, IL 60439 USA
[3] Argonne Natl Lab, Biosci, Argonne, IL 60439 USA
[4] Univ Texas El Paso, BLDg SCHOLARS,500 W Univ Ave, El Paso, TX 79968 USA
[5] UT Southwestern Med Ctr, Dept Biophys, Dallas, TX 75390 USA
[6] Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60367 USA
来源
CURRENT RESEARCH IN STRUCTURAL BIOLOGY | 2020年 / 2卷
基金
美国国家卫生研究院;
关键词
Nonribosomal peptide synthetase; Txo1; Txo2; Teixobactin; Condensation domain; Adenylation domain; Conformational change; alpha-helix regulation; Mg2+-binding; CRYSTAL-STRUCTURE; CONFORMATIONAL-CHANGES; THIOESTERASE DOMAIN; BIOSYNTHESIS; CYCLIZATION; BIOLOGY; CLONING; MODULE; MACROCYCLIZATION; MECHANISM;
D O I
10.1016/j.crstbi.2020.01.002
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 recently discovered antibiotic teixobactin is produced by uncultured soil bacteria. The antibiotic inhibits cell wall synthesis of Gram-positive bacteria by binding to precursors of cell wall building blocks, and therefore it is thought to be less vulnerable to development of resistance. Teixobactin is synthesized by two nonribosomal peptide synthetases (NRPSs), encoded by txo1 and txo2 genes. Like other NRPSs, the Txo1 and Txo2 synthetases are large, multifunctional, and comprised of several modules. Each module is responsible for catalysis of a distinct step of teixobactin synthesis and contains specific functional units, commonly including a condensation (C) domain, an adenylation (A) domain, and a peptidyl carrier protein (PCP) domain. Here we report the structures of the C-A bidomains of the two L-Ser condensing modules, from Txo1 and Txo2, respectively. In the structure of the C domain of the L-Ser subunit of Txo1, a large conformational change is observed, featuring an outward swing of its N-terminal alpha-helix. This repositioning, if functionally validated, provides the necessary conformational change for the condensation reaction in C domain, and likely represents a regulatory mechanism. In an A(core) subdomain, a well-coordinated Mg2+ cation is observed, which is required in the adenylation reaction. The Mg2+-binding site is defined by a largely conserved amino acid sequence motif and is coordinated by the alpha-phosphate group of AMP (or ATP) when present, providing some structural evidence for the role of the metal cation in the catalysis of A domain.
引用
收藏
页码:14 / 24
页数:11
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