4XGK

Crystal structure of UDP-galactopyranose mutase from Corynebacterium diphtheriae in complex with 2-[4-(4-chlorophenyl)-7-(2-thienyl)-2-thia-5,6,8,9-tetrazabicyclo[4.3.0]nona-4,7,9-trien-3-yl]acetic

Summary for 4XGK

• Entry DOI: 10.2210/pdb4xgk/pdb
• Descriptor: UDP-galactopyranose mutase, SULFATE ION, [(7S)-6-(4-chlorophenyl)-3-(thiophen-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-yl]acetic acid, ... (5 entities in total)
• Functional Keywords: udp-galactopyranose mutase, corynebacterium diphtheriae, inhibitor, galactofuranose, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Corynebacterium diphtheriae
• Total number of polymer chains: 2
• Total formula weight: 93345.25

Authors

Wangkanont, K.,Heroux, A.,Forest, K.T.,Kiessling, L.L. (deposition date: 2014-12-31, release date: 2015-08-12, Last modification date: 2023-09-27)

Primary citation

Kincaid, V.A.,London, N.,Wangkanont, K.,Wesener, D.A.,Marcus, S.A.,Heroux, A.,Nedyalkova, L.,Talaat, A.M.,Forest, K.T.,Shoichet, B.K.,Kiessling, L.L.
Virtual Screening for UDP-Galactopyranose Mutase Ligands Identifies a New Class of Antimycobacterial Agents.
Acs Chem.Biol., 10:2209-2218, 2015

PubMed Abstract: Galactofuranose (Galf) is present in glycans critical for the virulence and viability of several pathogenic microbes, including Mycobacterium tuberculosis, yet the monosaccharide is absent from mammalian glycans. Uridine 5'-diphosphate-galactopyranose mutase (UGM) catalyzes the formation of UDP-Galf, which is required to produce Galf-containing glycoconjugates. Inhibitors of UGM have therefore been sought, both as antimicrobial leads and as tools to delineate the roles of Galf in cells. Obtaining cell permeable UGM probes by either design or high throughput screens has been difficult, as has elucidating how UGM binds small molecule, noncarbohydrate inhibitors. To address these issues, we employed structure-based virtual screening to uncover new inhibitor chemotypes, including a triazolothiadiazine series. These compounds are among the most potent antimycobacterial UGM inhibitors described. They also facilitated determination of a UGM-small molecule inhibitor structure, which can guide optimization. A comparison of results from the computational screen and a high-throughput fluorescence polarization (FP) screen indicated that the scaffold hits from the former had been evaluated in the FP screen but missed. By focusing on promising compounds, the virtual screen rescued false negatives, providing a blueprint for generating new UGM probes and therapeutic leads.

PubMed: 26214585
DOI: 10.1021/acschembio.5b00370

Experimental method

X-RAY DIFFRACTION (2.652 Å)