4C70

Crystal structure of M. tuberculosis C171Q KasA in complex with TLM4

Summary for 4C70

• Entry DOI: 10.2210/pdb4c70/pdb
• Related: 4C6U 4C6V 4C6W 4C6X 4C6Z 4C71 4C72 4C73
• Descriptor: 3-OXOACYL-[ACYL-CARRIER-PROTEIN] SYNTHASE 1, GLYCEROL, ISOPROPYL ALCOHOL, ... (7 entities in total)
• Functional Keywords: transferase, kas enzyme, condensing enzyme, type 2 fatty acid biosynthesis, mycolic acid synthesis, thiolactomycin
• Biological source: MYCOBACTERIUM TUBERCULOSIS H37RV
• Total number of polymer chains: 2
• Total formula weight: 94144.84

Authors

Schiebel, J.,Kapilashrami, K.,Fekete, A.,Bommineni, G.R.,Schaefer, C.M.,Mueller, M.J.,Tonge, P.J.,Kisker, C. (deposition date: 2013-09-19, release date: 2013-10-09, Last modification date: 2023-12-20)

Primary citation

Schiebel, J.,Kapilashrami, K.,Fekete, A.,Bommineni, G.R.,Schaefer, C.M.,Mueller, M.J.,Tonge, P.J.,Kisker, C.
Structural Basis for the Recognition of Mycolic Acid Precursors by Kasa, a Condensing Enzyme and Drug Target from Mycobacterium Tuberculosis
J.Biol.Chem., 288:34190-, 2013

PubMed Abstract: The survival of Mycobacterium tuberculosis depends on mycolic acids, very long α-alkyl-β-hydroxy fatty acids comprising 60-90 carbon atoms. However, despite considerable efforts, little is known about how enzymes involved in mycolic acid biosynthesis recognize and bind their hydrophobic fatty acyl substrates. The condensing enzyme KasA is pivotal for the synthesis of very long (C38-42) fatty acids, the precursors of mycolic acids. To probe the mechanism of substrate and inhibitor recognition by KasA, we determined the structure of this protein in complex with a mycobacterial phospholipid and with several thiolactomycin derivatives that were designed as substrate analogs. Our structures provide consecutive snapshots along the reaction coordinate for the enzyme-catalyzed reaction and support an induced fit mechanism in which a wide cavity is established through the concerted opening of three gatekeeping residues and several α-helices. The stepwise characterization of the binding process provides mechanistic insights into the induced fit recognition in this system and serves as an excellent foundation for the development of high affinity KasA inhibitors.

PubMed: 24108128
DOI: 10.1074/JBC.M113.511436

Experimental method

X-RAY DIFFRACTION (1.75 Å)