7N8L

PptT PAP(CoA) 9016 complex

Summary for 7N8L

• Entry DOI: 10.2210/pdb7n8l/pdb
• Descriptor: 4'-phosphopantetheinyl transferase PptT, COENZYME A, N-(2,6-diethylphenyl)-N'-(N-propylcarbamimidoyl)urea, ... (7 entities in total)
• Functional Keywords: inhibitor, structural genomics, psi-biology, protein structure initiative, tb structural genomics consortium, tbsgc, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• Total number of polymer chains: 2
• Total formula weight: 55948.58

Authors

Mosior, J.W.,Sacchettini, J.C.,TB Structural Genomics Consortium (TBSGC) (deposition date: 2021-06-15, release date: 2022-02-02, Last modification date: 2023-10-18)

Primary citation

Ottavi, S.,Scarry, S.M.,Mosior, J.,Ling, Y.,Roberts, J.,Singh, A.,Zhang, D.,Goullieux, L.,Roubert, C.,Bacque, E.,Lagiakos, H.R.,Vendome, J.,Moraca, F.,Li, K.,Perkowski, A.J.,Ramesh, R.,Bowler, M.M.,Tracy, W.,Feher, V.A.,Sacchettini, J.C.,Gold, B.S.,Nathan, C.F.,Aube, J.
In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas.
J.Med.Chem., 65:1996-2022, 2022

PubMed Abstract: A newly validated target for tuberculosis treatment is phosphopantetheinyl transferase, an essential enzyme that plays a critical role in the biosynthesis of cellular lipids and virulence factors in . The structure-activity relationships of a recently disclosed inhibitor, amidinourea (AU) 8918 (), were explored, focusing on the biochemical potency, determination of whole-cell on-target activity for active compounds, and profiling of selective active congeners. These studies show that the AU moiety in AU 8918 is largely optimized and that potency enhancements are obtained in analogues containing a para-substituted aromatic ring. Preliminary data reveal that while some analogues, including , have demonstrated cardiotoxicity (e.g., changes in cardiomyocyte beat rate, amplitude, and peak width) and inhibit Ca1.2 and Na1.5 ion channels (although not hERG channels), inhibition of the ion channels is largely diminished for some of the para-substituted analogues, such as (-benzamide) and (-phenylsulfonamide).

PubMed: 35044775
DOI: 10.1021/acs.jmedchem.1c01565

Experimental method

X-RAY DIFFRACTION (2.26 Å)