5KDE

Inorganic pyrophosphatase from Mycobacterium tuberculosis in complex with inhibitor 1 and inorganic pyrophosphate

Summary for 5KDE

• Entry DOI: 10.2210/pdb5kde/pdb
• Related: 4Z74 5KDF
• Descriptor: Inorganic pyrophosphatase, 2,4-bis(aziridin-1-yl)-6-(1-phenylpyrrol-2-yl)-1,3,5-triazine, PYROPHOSPHATE 2-, ... (4 entities in total)
• Functional Keywords: hydrolase, pyrophosphatase, drug target, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• Cellular location: Cytoplasm : P9WI55
• Total number of polymer chains: 1
• Total formula weight: 19935.17

Authors

Pang, A.H.,Garzan, A.,Garneau-Tsodikova, S.,Tsodikov, O.V. (deposition date: 2016-06-08, release date: 2016-09-28, Last modification date: 2023-09-27)

Primary citation

Pang, A.H.,Garzan, A.,Larsen, M.J.,McQuade, T.J.,Garneau-Tsodikova, S.,Tsodikov, O.V.
Discovery of Allosteric and Selective Inhibitors of Inorganic Pyrophosphatase from Mycobacterium tuberculosis.
ACS Chem. Biol., 11:3084-3092, 2016

PubMed Abstract: Inorganic pyrophosphatase (PPiase) is an essential enzyme that hydrolyzes inorganic pyrophosphate (PP), driving numerous metabolic processes. We report a discovery of an allosteric inhibitor (2,4-bis(aziridin-1-yl)-6-(1-phenylpyrrol-2-yl)-s-triazine) of bacterial PPiases. Analogues of this lead compound were synthesized to target specifically Mycobacterium tuberculosis (Mtb) PPiase (MtPPiase). The best analogue (compound 16) with a K of 11 μM for MtPPiase is a species-specific inhibitor. Crystal structures of MtPPiase in complex with the lead compound and one of its analogues (compound 6) demonstrate that the inhibitors bind in a nonconserved interface between monomers of the hexameric MtPPiase in a yet unprecedented pairwise manner, while the remote conserved active site of the enzyme is occupied by a bound PP substrate. Consistent with the structural studies, the kinetic analysis of the most potent inhibitor has indicated that it functions uncompetitively, by binding to the enzyme-substrate complex. The inhibitors appear to allosterically lock the active site in a closed state causing its dysfunctionalization and blocking the hydrolysis. These inhibitors are the first examples of allosteric, species-selective inhibitors of PPiases, serving as a proof-of-principle that PPiases can be selectively targeted.

PubMed: 27622287
DOI: 10.1021/acschembio.6b00510

Experimental method

X-RAY DIFFRACTION (2.65 Å)