4BFW

Crystal structure of Mycobacterium tuberculosis PanK in complex with a triazole inhibitory compound (1e) and phosphate

Summary for 4BFW

• Entry DOI: 10.2210/pdb4bfw/pdb
• Related: 4BFS 4BFT 4BFU 4BFV 4BFX 4BFY 4BFZ
• Descriptor: PANTOTHENATE KINASE, PHOSPHATE ION, N-[1-(5-{[2-(4-fluorophenoxy)ethyl]sulfanyl}-4-[(4-fluorophenyl)methyl]-4H-1,2,4-triazol-3-yl)ethyl]-2-(trifluoromethyl)benzamide, ... (4 entities in total)
• Functional Keywords: transferase, coa pathway
• Biological source: MYCOBACTERIUM TUBERCULOSIS
• Total number of polymer chains: 2
• Total formula weight: 74382.50

Authors

Bjorkelid, C.,Bergfors, T.,Jones, T.A. (deposition date: 2013-03-22, release date: 2013-05-15, Last modification date: 2023-12-20)

Primary citation

Bjorkelid, C.,Bergfors, T.,Raichurkar, A.K.V.,Mukherjee, K.,Krishnan, M.,Bandodkar, B.,Jones, T.A.
Structural and Biochemical Characterization of Compounds Inhibiting Mycobacterium Tuberculosis Pank
J.Biol.Chem., 288:18260-, 2013

PubMed Abstract: Mycobacterium tuberculosis, the bacterial causative agent of tuberculosis, currently affects millions of people. The emergence of drug-resistant strains makes development of new antibiotics targeting the bacterium a global health priority. Pantothenate kinase, a key enzyme in the universal biosynthesis of the essential cofactor CoA, was targeted in this study to find new tuberculosis drugs. The biochemical characterizations of two new classes of compounds that inhibit pantothenate kinase from M. tuberculosis are described, along with crystal structures of their enzyme-inhibitor complexes. These represent the first crystal structures of this enzyme with engineered inhibitors. Both classes of compounds bind in the active site of the enzyme, overlapping with the binding sites of the natural substrate and product, pantothenate and phosphopantothenate, respectively. One class of compounds also interferes with binding of the cofactor ATP. The complexes were crystallized in two crystal forms, one of which is in a new space group for this enzyme and diffracts to the highest resolution reported for any pantothenate kinase structure. These two crystal forms allowed, for the first time, modeling of the cofactor-binding loop in both open and closed conformations. The structures also show a binding mode of ATP different from that previously reported for the M. tuberculosis enzyme but similar to that in the pantothenate kinases of other organisms.

PubMed: 23661699
DOI: 10.1074/JBC.M113.476473

Experimental method

X-RAY DIFFRACTION (2.27 Å)