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4giu

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==Bianthranilate-like analogue bound in inner site of anthranilate phosphoribosyltransferase (AnPRT; trpD).==
==Bianthranilate-like analogue bound in inner site of anthranilate phosphoribosyltransferase (AnPRT; trpD).==
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<StructureSection load='4giu' size='340' side='right' caption='[[4giu]], [[Resolution|resolution]] 1.67&Aring;' scene=''>
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<StructureSection load='4giu' size='340' side='right'caption='[[4giu]], [[Resolution|resolution]] 1.67&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4giu]] 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=4GIU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GIU FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4giu]] 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=4GIU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GIU FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=636:2-[(2-CARBOXY-5-METHYLPHENYL)AMINO]-3-METHYLBENZOIC+ACID'>636</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>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.667&#8491;</td></tr>
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<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=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=636:2-[(2-CARBOXY-5-METHYLPHENYL)AMINO]-3-METHYLBENZOIC+ACID'>636</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>
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<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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4giu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4giu OCA], [https://pdbe.org/4giu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4giu RCSB], [https://www.ebi.ac.uk/pdbsum/4giu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4giu ProSAT]</span></td></tr>
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<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=4giu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4giu OCA], [http://pdbe.org/4giu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4giu RCSB], [http://www.ebi.ac.uk/pdbsum/4giu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4giu ProSAT]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/TRPD_MYCTU TRPD_MYCTU]
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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.
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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<ref>PMID:24623674</ref>
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==See Also==
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*[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4giu" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Anthranilate phosphoribosyltransferase]]
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[[Category: Large Structures]]
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[[Category: Baker, E N]]
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[[Category: Mycobacterium tuberculosis]]
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[[Category: Evans, G L]]
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[[Category: Baker EN]]
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[[Category: Lott, J S]]
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[[Category: Evans GL]]
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[[Category: Structural genomic]]
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[[Category: Lott JS]]
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[[Category: Bi-anthranilate-like analogue]]
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[[Category: Inhibitor complex]]
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[[Category: Magnesium binding]]
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[[Category: Phophoribosylpyrophosphate]]
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[[Category: Phosphoribosyltransferase]]
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[[Category: Prpp]]
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[[Category: Tbsgc]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Bianthranilate-like analogue bound in inner site of anthranilate phosphoribosyltransferase (AnPRT; trpD).

PDB ID 4giu

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