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| | ==Bianthranilate-like analogue bound in the outer site of anthranilate phosphoribosyltransferase (AnPRT; trpD)== | | ==Bianthranilate-like analogue bound in the outer site of anthranilate phosphoribosyltransferase (AnPRT; trpD)== |
| - | <StructureSection load='4gkm' size='340' side='right' caption='[[4gkm]], [[Resolution|resolution]] 1.67Å' scene=''> | + | <StructureSection load='4gkm' size='340' side='right'caption='[[4gkm]], [[Resolution|resolution]] 1.67Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4gkm]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GKM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GKM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4gkm]] is a 2 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=4GKM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GKM FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=683:2-[(2-CARBOXYPHENYL)AMINO]-5-METHYLBENZOIC+ACID'>683</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PRP:ALPHA-PHOSPHORIBOSYLPYROPHOSPHORIC+ACID'>PRP</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=683:2-[(2-CARBOXYPHENYL)AMINO]-5-METHYLBENZOIC+ACID'>683</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PRP:ALPHA-PHOSPHORIBOSYLPYROPHOSPHORIC+ACID'>PRP</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4giu|4giu]]</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=4gkm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gkm OCA], [https://pdbe.org/4gkm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gkm RCSB], [https://www.ebi.ac.uk/pdbsum/4gkm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gkm ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MT2248, MTCY190.03c, Rv2192c, trpD ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Anthranilate_phosphoribosyltransferase Anthranilate phosphoribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.18 2.4.2.18] </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=4gkm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gkm OCA], [http://pdbe.org/4gkm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4gkm RCSB], [http://www.ebi.ac.uk/pdbsum/4gkm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4gkm ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/TRPD_MYCTU TRPD_MYCTU] |
| | <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 4gkm" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4gkm" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Anthranilate phosphoribosyltransferase]] | + | [[Category: Large Structures]] |
| - | [[Category: Myctu]] | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Baker, E N]] | + | [[Category: Baker EN]] |
| - | [[Category: Evans, G L]] | + | [[Category: Evans GL]] |
| - | [[Category: Lott, J S]] | + | [[Category: Lott JS]] |
| - | [[Category: Structural genomic]]
| + | |
| - | [[Category: Bi-anthranilate-like analogue]]
| + | |
| - | [[Category: Inhibitor complex]]
| + | |
| - | [[Category: Magnesium binding]]
| + | |
| - | [[Category: Phosphoribosylpyrophosphate]]
| + | |
| - | [[Category: Phosphoribosyltransferase]]
| + | |
| - | [[Category: Prpp]]
| + | |
| - | [[Category: Tbsgc]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
TRPD_MYCTU
Publication Abstract from PubMed
The emergence of extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb) highlights the need for new therapeutics to treat tuberculosis. We are attempting to fast-track a targeted approach to drug design by generating analogues of a validated hit from molecular library screening that shares its chemical scaffold with a current therapeutic, the anti-arthritic drug Lobenzarit (LBZ). Our target, anthranilate phosphoribosyltransferase (AnPRT), is an enzyme from the tryptophan biosynthetic pathway in Mtb. A bifurcated hydrogen bond was found to be a key feature of the LBZ-like chemical scaffold and critical for enzyme inhibition. We have determined crystal structures of compounds in complex with the enzyme that indicate that the bifurcated hydrogen bond assists in orientating compounds in the correct conformation to interact with key residues in the substrate-binding tunnel of Mtb-AnPRT. Characterising the inhibitory potency of the hit and its analogues in different ways proved useful, due to the multiple substrates and substrate binding sites of this enzyme. Binding in a site other than the catalytic site was found to be associated with partial inhibition. An analogue, 2-(2-5-methylcarboxyphenylamino)-3-methylbenzoic acid, that bound at the catalytic site and caused complete, rather than partial, inhibition of enzyme activity was found. Therefore, we designed and synthesised an extended version of the scaffold on the basis of this observation. The resultant compound, 2,6-bis-(2-carboxyphenylamino)benzoate, is a 40-fold more potent inhibitor of the enzyme than the original hit and provides direction for further structure-based drug design.
Repurposing the chemical scaffold of the anti-arthritic drug Lobenzarit to target tryptophan biosynthesis in Mycobacterium tuberculosis.,Evans GL, Gamage SA, Bulloch EM, Baker EN, Denny WA, Lott JS Chembiochem. 2014 Apr 14;15(6):852-64. doi: 10.1002/cbic.201300628. Epub 2014 Mar, 12. PMID:24623674[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Evans GL, Gamage SA, Bulloch EM, Baker EN, Denny WA, Lott JS. Repurposing the chemical scaffold of the anti-arthritic drug Lobenzarit to target tryptophan biosynthesis in Mycobacterium tuberculosis. Chembiochem. 2014 Apr 14;15(6):852-64. doi: 10.1002/cbic.201300628. Epub 2014 Mar, 12. PMID:24623674 doi:http://dx.doi.org/10.1002/cbic.201300628
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