5V3Y

Crystal Structure of Mtb Pks13 Thioesterase domain in complex with inhibitor TAM16

5V3Y の概要

• エントリーDOI: 10.2210/pdb5v3y/pdb
• 関連するPDBエントリー: 5V3W 5V3X 5V3Z 5V40 5V41 5V42
• 分子名称: Polyketide synthase Pks13 (Termination polyketide synthase), 2-(4-hydroxyphenyl)-~{N}-methyl-5-oxidanyl-4-(piperidin-1-ylmethyl)-1-benzofuran-3-carboxamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: thioesterase domain, tam16 complex, pks13, mycobacterium, polyketide synthase, mycolic acid condensation, tb structural genomics consortium, tbsgc, alpha/beta hydrolase, thioesterase-transferase inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 64412.42

構造登録者

Aggarwal, A.,Sacchettini, J.C. (登録日: 2017-03-08, 公開日: 2017-07-05, 最終更新日: 2023-10-04)

主引用文献

Aggarwal, A.,Parai, M.K.,Shetty, N.,Wallis, D.,Woolhiser, L.,Hastings, C.,Dutta, N.K.,Galaviz, S.,Dhakal, R.C.,Shrestha, R.,Wakabayashi, S.,Walpole, C.,Matthews, D.,Floyd, D.,Scullion, P.,Riley, J.,Epemolu, O.,Norval, S.,Snavely, T.,Robertson, G.T.,Rubin, E.J.,Ioerger, T.R.,Sirgel, F.A.,van der Merwe, R.,van Helden, P.D.,Keller, P.,Bottger, E.C.,Karakousis, P.C.,Lenaerts, A.J.,Sacchettini, J.C.
Development of a Novel Lead that Targets M. tuberculosis Polyketide Synthase 13.
Cell, 170:249-259.e25, 2017

PubMed Abstract: Widespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, required for the cell wall of Mycobacterium tuberculosis. Our lead, TAM16, is a benzofuran class inhibitor of Pks13 with highly potent in vitro bactericidal activity against drug-susceptible and drug-resistant clinical isolates of M. tuberculosis. In multiple mouse models of TB infection, TAM16 showed in vivo efficacy equal to the first-line TB drug isoniazid, both as a monotherapy and in combination therapy with rifampicin. TAM16 has excellent pharmacological and safety profiles, and the frequency of resistance for TAM16 is ∼100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection. PAPERCLIP.

PubMed: 28669536
DOI: 10.1016/j.cell.2017.06.025

実験手法

X-RAY DIFFRACTION (1.98 Å)