8GKF

Phosphopantetheinyl transferase PptT from Mycobacterium tuberculosis in complex with Raltitrexed.

Summary for 8GKF

• Entry DOI: 10.2210/pdb8gkf/pdb
• Descriptor: 4'-phosphopantetheinyl transferase PptT, TOMUDEX (3 entities in total)
• Functional Keywords: complex, inhibitor, drug, structural genomics, tb structural genomics consortium, tbsgc, transferase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 9
• Total formula weight: 235070.63

Authors

Krieger, I.V.,Singh, A.,Sacchettini, J.C.,TB Structural Genomics Consortium (TBSGC) (deposition date: 2023-03-18, release date: 2024-03-20, Last modification date: 2024-03-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.45 Å)