7q52

From Proteopedia

(Difference between revisions)

Revision as of 07:18, 8 September 2022

Crystal structure of S/T protein kinase PknG from Mycobacterium tuberculosis in complex with inhibitor L2W

Structural highlights

7q52 is a 1 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PKNG_MYCTU] Phosphorylates GarA. May play a role in metabolic regulation via control of the phosphorylation status of GarA. Plays a crucial role in the survival of mycobacteria within host macrophages, by blocking the intracellular degradation of mycobacteria in lysosomes. Required for intrinsic antibiotic resistance.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Computer-aided drug discovery methods play a major role in the development of therapeutically important small molecules, but their performance needs to be improved. Molecular dynamics simulations in mixed solvents are useful in understanding protein-ligand recognition and improving molecular docking predictions. In this work, we used ethanol as a cosolvent to find relevant interactions for ligands toward protein kinase G, an essential protein of Mycobacterium tuberculosis (Mtb). We validated the hot spots by screening a database of fragment-like compounds and another one of known kinase inhibitors. Next, we performed a pharmacophore-guided docking simulation and found three low micromolar inhibitors, including one with a novel chemical scaffold that we expanded to four derivative compounds. Binding affinities were characterized by intrinsic fluorescence quenching assays, isothermal titration calorimetry, and the analysis of melting curves. The predicted binding mode was confirmed by X-ray crystallography. Finally, the compounds significantly inhibited the viability of Mtb in infected THP-1 macrophages.

Cosolvent Sites-Based Discovery of Mycobacterium Tuberculosis Protein Kinase G Inhibitors.,Burastero O, Defelipe LA, Gola G, Tateosian NL, Lopez ED, Martinena CB, Arcon JP, Traian MD, Wetzler DE, Bento I, Barril X, Ramirez J, Marti MA, Garcia-Alai MM, Turjanski AG J Med Chem. 2022 Jun 23. doi: 10.1021/acs.jmedchem.1c02012. PMID:35737472^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ O'Hare HM, Duran R, Cervenansky C, Bellinzoni M, Wehenkel AM, Pritsch O, Obal G, Baumgartner J, Vialaret J, Johnsson K, Alzari PM. Regulation of glutamate metabolism by protein kinases in mycobacteria. Mol Microbiol. 2008 Dec;70(6):1408-23. doi: 10.1111/j.1365-2958.2008.06489.x., Epub 2008 Oct 17. PMID:19019160 doi:http://dx.doi.org/10.1111/j.1365-2958.2008.06489.x
↑ Wolff KA, Nguyen HT, Cartabuke RH, Singh A, Ogwang S, Nguyen L. Protein kinase G is required for intrinsic antibiotic resistance in mycobacteria. Antimicrob Agents Chemother. 2009 Aug;53(8):3515-9. doi: 10.1128/AAC.00012-09., Epub 2009 Jun 15. PMID:19528288 doi:http://dx.doi.org/10.1128/AAC.00012-09
↑ Tiwari D, Singh RK, Goswami K, Verma SK, Prakash B, Nandicoori VK. Key residues in Mycobacterium tuberculosis protein kinase G play a role in regulating kinase activity and survival in the host. J Biol Chem. 2009 Oct 2;284(40):27467-79. doi: 10.1074/jbc.M109.036095. Epub 2009, Jul 28. PMID:19638631 doi:http://dx.doi.org/10.1074/jbc.M109.036095
↑ Scherr N, Honnappa S, Kunz G, Mueller P, Jayachandran R, Winkler F, Pieters J, Steinmetz MO. Structural basis for the specific inhibition of protein kinase G, a virulence factor of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12151-6. Epub 2007 Jul 6. PMID:17616581
↑ Burastero O, Defelipe LA, Gola G, Tateosian NL, Lopez ED, Martinena CB, Arcon JP, Traian MD, Wetzler DE, Bento I, Barril X, Ramirez J, Marti MA, Garcia-Alai MM, Turjanski AG. Cosolvent Sites-Based Discovery of Mycobacterium Tuberculosis Protein Kinase G Inhibitors. J Med Chem. 2022 Jun 23. doi: 10.1021/acs.jmedchem.1c02012. PMID:35737472 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c02012

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7q52"

@@ Line 3: / Line 3: @@
 <StructureSection load='7q52' size='340' side='right'caption='[[7q52]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7q52]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7Q52 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Q52 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7q52]] 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=7Q52 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Q52 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8ZC:2-azanyl-3-(4-fluorophenyl)carbonyl-indolizine-1-carboxamide'>8ZC</scene>, <scene name='pdbligand=FE:FE+(III)+ION'>FE</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></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=7q52 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7q52 OCA], [https://pdbe.org/7q52 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7q52 RCSB], [https://www.ebi.ac.uk/pdbsum/7q52 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7q52 ProSAT]</span></td></tr>
 </table>
 == Function ==
 [[https://www.uniprot.org/uniprot/PKNG_MYCTU PKNG_MYCTU]] Phosphorylates GarA. May play a role in metabolic regulation via control of the phosphorylation status of GarA. Plays a crucial role in the survival of mycobacteria within host macrophages, by blocking the intracellular degradation of mycobacteria in lysosomes. Required for intrinsic antibiotic resistance.<ref>PMID:19019160</ref> <ref>PMID:19528288</ref> <ref>PMID:19638631</ref> <ref>PMID:17616581</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 24: / Line 23: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Mycobacterium tuberculosis H37Rv]]
-[[Category: Bento, I]]
+[[Category: Bento I]]
-[[Category: Burastero, O]]
+[[Category: Burastero O]]
-[[Category: Defelipe, L A]]
+[[Category: Defelipe LA]]
-[[Category: Garcia-Alai, M M]]
+[[Category: Garcia-Alai MM]]
-[[Category: Inhibitor]]
-[[Category: L2w]]
-[[Category: Transferase]]
-[[Category: Tuberculosis]]

7q52

From Proteopedia

Revision as of 07:18, 8 September 2022

Crystal structure of S/T protein kinase PknG from Mycobacterium tuberculosis in complex with inhibitor L2W

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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