5kde: Difference between revisions
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The | ==Inorganic pyrophosphatase from Mycobacterium tuberculosis in complex with inhibitor 1 and inorganic pyrophosphate== | ||
<StructureSection load='5kde' size='340' side='right'caption='[[5kde]], [[Resolution|resolution]] 2.65Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5kde]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KDE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KDE FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.65Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6RT:2,4-BIS(AZIRIDIN-1-YL)-6-(1-PHENYLPYRROL-2-YL)-1,3,5-TRIAZINE'>6RT</scene>, <scene name='pdbligand=POP:PYROPHOSPHATE+2-'>POP</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5kde FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kde OCA], [https://pdbe.org/5kde PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5kde RCSB], [https://www.ebi.ac.uk/pdbsum/5kde PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5kde ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/IPYR_MYCTU IPYR_MYCTU] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Inorganic pyrophosphatase (PPiase) is an essential enzyme that hydrolyzes inorganic pyrophosphate (PPi), 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 Ki of 11 muM 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 PPi 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. | |||
Discovery of Allosteric and Selective Inhibitors of Inorganic Pyrophosphatase from Mycobacterium tuberculosis.,Pang AH, Garzan A, Larsen MJ, McQuade TJ, Garneau-Tsodikova S, Tsodikov OV ACS Chem Biol. 2016 Sep 26. PMID:27622287<ref>PMID:27622287</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5kde" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Inorganic pyrophosphatase 3D structures|Inorganic pyrophosphatase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mycobacterium tuberculosis H37Rv]] | |||
[[Category: Garneau-Tsodikova S]] | |||
[[Category: Garzan A]] | |||
[[Category: Pang AH]] | |||
[[Category: Tsodikov OV]] | |||
Latest revision as of 12:58, 27 September 2023
Inorganic pyrophosphatase from Mycobacterium tuberculosis in complex with inhibitor 1 and inorganic pyrophosphateInorganic pyrophosphatase from Mycobacterium tuberculosis in complex with inhibitor 1 and inorganic pyrophosphate
Structural highlights
FunctionPublication Abstract from PubMedInorganic pyrophosphatase (PPiase) is an essential enzyme that hydrolyzes inorganic pyrophosphate (PPi), 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 Ki of 11 muM 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 PPi 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. Discovery of Allosteric and Selective Inhibitors of Inorganic Pyrophosphatase from Mycobacterium tuberculosis.,Pang AH, Garzan A, Larsen MJ, McQuade TJ, Garneau-Tsodikova S, Tsodikov OV ACS Chem Biol. 2016 Sep 26. PMID:27622287[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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