6CT5

PptT PAP(CoA) 8918 complex

Summary for 6CT5

• Entry DOI: 10.2210/pdb6ct5/pdb
• Descriptor: 4'-phosphopantetheinyl transferase, COENZYME A, N-(2,6-diethylphenyl)-N'-(N-ethylcarbamimidoyl)urea, ... (7 entities in total)
• Functional Keywords: inhibitor, complex, structural genomics, tb structural genomics consortium, tbsgc, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 56976.57

Authors

Mosior, J.,Sacchettini, J.,TB Structural Genomics Consortium (TBSGC) (deposition date: 2018-03-22, release date: 2019-02-06, Last modification date: 2023-10-04)

Primary citation

Ballinger, E.,Mosior, J.,Hartman, T.,Burns-Huang, K.,Gold, B.,Morris, R.,Goullieux, L.,Blanc, I.,Vaubourgeix, J.,Lagrange, S.,Fraisse, L.,Sans, S.,Couturier, C.,Bacque, E.,Rhee, K.,Scarry, S.M.,Aube, J.,Yang, G.,Ouerfelli, O.,Schnappinger, D.,Ioerger, T.R.,Engelhart, C.A.,McConnell, J.A.,McAulay, K.,Fay, A.,Roubert, C.,Sacchettini, J.,Nathan, C.
Opposing reactions in coenzyme A metabolism sensitizeMycobacterium tuberculosisto enzyme inhibition.
Science, 363:-, 2019

PubMed Abstract: (Mtb) is the leading infectious cause of death in humans. Synthesis of lipids critical for Mtb's cell wall and virulence depends on phosphopantetheinyl transferase (PptT), an enzyme that transfers 4'-phosphopantetheine (Ppt) from coenzyme A (CoA) to diverse acyl carrier proteins. We identified a compound that kills Mtb by binding and partially inhibiting PptT. Killing of Mtb by the compound is potentiated by another enzyme encoded in the same operon, Ppt hydrolase (PptH), that undoes the PptT reaction. Thus, loss-of-function mutants of PptH displayed antimicrobial resistance. Our PptT-inhibitor cocrystal structure may aid further development of antimycobacterial agents against this long-sought target. The opposing reactions of PptT and PptH uncover a regulatory pathway in CoA physiology.

PubMed: 30705156
DOI: 10.1126/science.aau8959

Experimental method

X-RAY DIFFRACTION (1.75934602056 Å)