8TQV

Crystal Structure of Mtb Pks13 Thioesterase domain in complex with inhibitor X20403

Summary for 8TQV

• Entry DOI: 10.2210/pdb8tqv/pdb
• Descriptor: Polyketide synthase Pks13, 4-(2-{(4M)-4-[(6M)-6-(2,5-dimethoxyphenyl)pyridin-3-yl]-1H-1,2,3-triazol-1-yl}ethyl)-N-{[1-(methoxymethyl)cyclopropyl]methyl}-N-methylbenzamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: polyketide synthase, thioesterase, biosynthetic protein
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 2
• Total formula weight: 62760.69

Authors

Krieger, I.V.,Sacchettini, J.C. (deposition date: 2023-08-08, release date: 2024-04-24, Last modification date: 2024-05-22)

Primary citation

Krieger, I.V.,Yalamanchili, S.,Dickson, P.,Engelhart, C.A.,Zimmerman, M.D.,Wood, J.,Clary, E.,Nguyen, J.,Thornton, N.,Centrella, P.A.,Chan, B.,Cuozzo, J.W.,Gengenbacher, M.,Guie, M.A.,Guilinger, J.P.,Bienstock, C.,Hartl, H.,Hupp, C.D.,Jetson, R.,Satoh, T.,Yeoman, J.T.S.,Zhang, Y.,Dartois, V.,Schnappinger, D.,Keefe, A.D.,Sacchettini, J.C.
Inhibitors of the Thioesterase Activity of Mycobacterium tuberculosis Pks13 Discovered Using DNA-Encoded Chemical Library Screening.
Acs Infect Dis., 10:1561-1575, 2024

PubMed Abstract: DNA-encoded chemical library (DEL) technology provides a time- and cost-efficient method to simultaneously screen billions of compounds for their affinity to a protein target of interest. Here we report its use to identify a novel chemical series of inhibitors of the thioesterase activity of polyketide synthase 13 (Pks13) from (Mtb). We present three chemically distinct series of inhibitors along with their enzymatic and Mtb whole cell potency, the measure of on-target activity in cells, and the crystal structures of inhibitor-enzyme complexes illuminating their interactions with the active site of the enzyme. One of these inhibitors showed a favorable pharmacokinetic profile and demonstrated efficacy in an acute mouse model of tuberculosis (TB) infection. These findings and assay developments will aid in the advancement of TB drug discovery.

PubMed: 38577994
DOI: 10.1021/acsinfecdis.3c00592

Experimental method

X-RAY DIFFRACTION (2 Å)