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| | <StructureSection load='6c9v' size='340' side='right'caption='[[6c9v]], [[Resolution|resolution]] 1.70Å' scene=''> | | <StructureSection load='6c9v' size='340' side='right'caption='[[6c9v]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6c9v]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6C9V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6C9V FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6c9v]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6C9V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6C9V FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ERS:(2R,3S,4R,5R)-2-(hydroxymethyl)-5-[6-(4-phenylpiperazin-1-yl)-9H-purin-9-yl]tetrahydrofuran-3,4-diol'>ERS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">adoK, cbhK, MRA_2218 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ERS:(2R,3S,4R,5R)-2-(hydroxymethyl)-5-[6-(4-phenylpiperazin-1-yl)-9H-purin-9-yl]tetrahydrofuran-3,4-diol'>ERS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Adenosine_kinase Adenosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.20 2.7.1.20] </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=6c9v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6c9v OCA], [https://pdbe.org/6c9v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6c9v RCSB], [https://www.ebi.ac.uk/pdbsum/6c9v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6c9v ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6c9v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6c9v OCA], [http://pdbe.org/6c9v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6c9v RCSB], [http://www.ebi.ac.uk/pdbsum/6c9v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6c9v ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ADOK_MYCTA ADOK_MYCTA]] Catalyzes the phosphorylation of adenosine to adenosine monophosphate (AMP). Can also catalyze the phosphorylation of the adenosine analog 2-methyladenosine (methyl-Ado) to methyl-AMP, the first step in the metabolism of this compound to an active form that displays antitubercular activity. Is not active on guanosine, inosine, deoxyadenosine, cytidine, uridine, or thymidine. Prefers dGTP and GTP to ATP as phosphate donors in vitro.<ref>PMID:14594827</ref> | + | [https://www.uniprot.org/uniprot/ADOK_MYCTU ADOK_MYCTU] ATP dependent phosphorylation of adenosine to monophosphate derivatives (By similarity). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6c9v" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6c9v" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Adenosine kinase 3D structures|Adenosine kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Adenosine kinase]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Crespo, R A]] | + | [[Category: Mycobacterium tuberculosis]] |
| - | [[Category: Structural genomic]] | + | [[Category: Crespo RA]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Nucleoside analog]]
| + | |
| - | [[Category: PSI, Protein structure initiative]]
| + | |
| - | [[Category: Tbsgc]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
ADOK_MYCTU ATP dependent phosphorylation of adenosine to monophosphate derivatives (By similarity).
Publication Abstract from PubMed
Mycobacterium tuberculosis adenosine kinase (MtbAdoK) is an essential enzyme of Mtb and forms part of the purine salvage pathway within mycobacteria. Evidence suggests that the purine salvage pathway might play a crucial role in Mtb survival and persistence during its latent phase of infection. In these studies, we adopted a structural approach to the discovery, structure-guided design, and synthesis of a series of adenosine analogues that displayed inhibition constants ranging from 5 to 120 nM against the enzyme. Two of these compounds exhibited low micromolar activity against Mtb with half maximal effective inhibitory concentrations of 1.7 and 4.0 muM. Our selectivity and preliminary pharmacokinetic studies showed that the compounds possess a higher degree of specificity against MtbAdoK when compared with the human counterpart and are well tolerated in rodents, respectively. Finally, crystallographic studies showed the molecular basis of inhibition, potency, and selectivity and revealed the presence of a potentially therapeutically relevant cavity unique to the MtbAdoK homodimer.
Structure-Guided Drug Design of 6-Substituted Adenosine Analogues as Potent Inhibitors of Mycobacterium tuberculosis Adenosine Kinase.,Crespo RA, Dang Q, Zhou NE, Guthrie LM, Snavely TC, Dong W, Loesch KA, Suzuki T, You L, Wang W, O'Malley T, Parish T, Olsen DB, Sacchettini JC J Med Chem. 2019 Apr 19. doi: 10.1021/acs.jmedchem.9b00020. PMID:31002508[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Crespo RA, Dang Q, Zhou NE, Guthrie LM, Snavely TC, Dong W, Loesch KA, Suzuki T, You L, Wang W, O'Malley T, Parish T, Olsen DB, Sacchettini JC. Structure-Guided Drug Design of 6-Substituted Adenosine Analogues as Potent Inhibitors of Mycobacterium tuberculosis Adenosine Kinase. J Med Chem. 2019 Apr 19. doi: 10.1021/acs.jmedchem.9b00020. PMID:31002508 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00020
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