8GKF

Phosphopantetheinyl transferase PptT from Mycobacterium tuberculosis in complex with Raltitrexed.

8GKF の概要

• エントリーDOI: 10.2210/pdb8gkf/pdb
• 分子名称: 4'-phosphopantetheinyl transferase PptT, TOMUDEX (3 entities in total)
• 機能のキーワード: complex, inhibitor, drug, structural genomics, tb structural genomics consortium, tbsgc, transferase
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 235070.63

構造登録者

Krieger, I.V.,Singh, A.,Sacchettini, J.C.,TB Structural Genomics Consortium (TBSGC) (登録日: 2023-03-18, 公開日: 2024-03-20, 最終更新日: 2024-03-27)

主引用文献

Singh, A.,Ottavi, S.,Krieger, I.,Planck, K.,Perkowski, A.,Kaneko, T.,Davis, A.M.,Suh, C.,Zhang, D.,Goullieux, L.,Alex, A.,Roubert, C.,Gardner, M.,Preston, M.,Smith, D.M.,Ling, Y.,Roberts, J.,Cautain, B.,Upton, A.,Cooper, C.B.,Serbina, N.,Tanvir, Z.,Mosior, J.,Ouerfelli, O.,Yang, G.,Gold, B.S.,Rhee, K.Y.,Sacchettini, J.C.,Fotouhi, N.,Aube, J.,Nathan, C.
Redirecting raltitrexed from cancer cell thymidylate synthase to Mycobacterium tuberculosis phosphopantetheinyl transferase.
Sci Adv, 10:eadj6406-eadj6406, 2024

PubMed Abstract: There is a compelling need to find drugs active against (). 4'-Phosphopantetheinyl transferase (PptT) is an essential enzyme in that has attracted interest as a potential drug target. We optimized a PptT assay, used it to screen 422,740 compounds, and identified raltitrexed, an antineoplastic antimetabolite, as the most potent PptT inhibitor yet reported. While trying unsuccessfully to improve raltitrexed's ability to kill and remove its ability to kill human cells, we learned three lessons that may help others developing antibiotics. First, binding of raltitrexed substantially changed the configuration of the PptT active site, complicating molecular modeling of analogs based on the unliganded crystal structure or the structure of cocrystals with inhibitors of another class. Second, minor changes in the raltitrexed molecule changed its target in from PptT to dihydrofolate reductase (DHFR). Third, the structure-activity relationship for over 800 raltitrexed analogs only became interpretable when we quantified and characterized the compounds' intrabacterial accumulation and transformation.

PubMed: 38489355
DOI: 10.1126/sciadv.adj6406

実験手法

X-RAY DIFFRACTION (2.45 Å)