5W2O

Crystal structure of Mycobacterium tuberculosis KasA

5W2O の概要

• エントリーDOI: 10.2210/pdb5w2o/pdb
• 関連するPDBエントリー: 2WGD 2WGE 2WGF 2WGG 4C6U 4C6V 4C6W 4C6X 4C6Z 4C70 4C71 4C72 4C73 5LD8
• 分子名称: 3-oxoacyl-[acyl-carrier-protein] synthase 1, SODIUM ION, GLYCEROL, ... (7 entities in total)
• 機能のキーワード: beta ketoacyl synthase i, lipid synthesis, fatty acid biosynthesis, transferase
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 35801 / TMC 107 / Erdman)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46645.92

構造登録者

Capodagli, G.C.,Neiditch, M.B. (登録日: 2017-06-06, 公開日: 2018-12-05, 最終更新日: 2023-10-04)

主引用文献

Kumar, P.,Capodagli, G.C.,Awasthi, D.,Shrestha, R.,Maharaja, K.,Sukheja, P.,Li, S.G.,Inoyama, D.,Zimmerman, M.,Ho Liang, H.P.,Sarathy, J.,Mina, M.,Rasic, G.,Russo, R.,Perryman, A.L.,Richmann, T.,Gupta, A.,Singleton, E.,Verma, S.,Husain, S.,Soteropoulos, P.,Wang, Z.,Morris, R.,Porter, G.,Agnihotri, G.,Salgame, P.,Ekins, S.,Rhee, K.Y.,Connell, N.,Dartois, V.,Neiditch, M.B.,Freundlich, J.S.,Alland, D.
Synergistic Lethality of a Binary Inhibitor of Mycobacterium tuberculosis KasA.
MBio, 9:-, 2018

PubMed Abstract: We report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) in Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-Å resolution revealed two interacting DG167 molecules occupying nonidentical sites in the substrate-binding channel of KasA. The binding affinities of KasA to DG167 and its analog, 5g, which binds only once in the substrate-binding channel, were determined, along with the KasA-5g X-ray crystal structure. DG167 strongly augmented the activity of isoniazid (INH), leading to synergistic lethality, and also synergized in an acute mouse model of infection. Synergistic lethality correlated with a unique transcriptional signature, including upregulation of oxidoreductases and downregulation of molecular chaperones. The lead structure-activity relationships (SAR), pharmacokinetic profile, and detailed interactions with the KasA protein that we describe may be applied to evolve a next-generation therapeutic strategy for tuberculosis (TB). Cell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors of KasA-a key component for biosynthesis of the mycolic acid layer of the bacterium's cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). One lead compound, DG167, demonstrated synergistic lethality in combination with INH and a transcriptional pattern consistent with bactericidality and loss of persisters. Our results also detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities. Together, these results suggest that KasA inhibition, specifically, that shown by the DG167 series, may be developed into a potent therapy that can synergize with existing antituberculars.

PubMed: 30563908
DOI: 10.1128/mBio.02101-17

実験手法

X-RAY DIFFRACTION (1.8 Å)