4ij1: Difference between revisions
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==Bianthranilate-like analogue bound to anthranilate phosphoribosyltransferase (AnPRT; trpD) in absence of substrates.== | ==Bianthranilate-like analogue bound to anthranilate phosphoribosyltransferase (AnPRT; trpD) in absence of substrates.== | ||
<StructureSection load='4ij1' size='340' side='right' caption='[[4ij1]], [[Resolution|resolution]] 1.79Å' scene=''> | <StructureSection load='4ij1' size='340' side='right'caption='[[4ij1]], [[Resolution|resolution]] 1.79Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4ij1]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4ij1]] 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=4IJ1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IJ1 FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.79Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=17C:2,2-IMINODIBENZOIC+ACID'>17C</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene></td></tr> | |||
<tr id=' | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ij1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ij1 OCA], [https://pdbe.org/4ij1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ij1 RCSB], [https://www.ebi.ac.uk/pdbsum/4ij1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ij1 ProSAT]</span></td></tr> | ||
< | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</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 == | ||
| Line 21: | Line 21: | ||
==See Also== | ==See Also== | ||
*[[Phosphoribosyltransferase|Phosphoribosyltransferase]] | *[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Mycobacterium tuberculosis]] | ||
[[Category: | [[Category: Baker EN]] | ||
[[Category: | [[Category: Evans GL]] | ||
[[Category: | [[Category: Lott JS]] | ||
Latest revision as of 18:24, 20 September 2023
Bianthranilate-like analogue bound to anthranilate phosphoribosyltransferase (AnPRT; trpD) in absence of substrates.Bianthranilate-like analogue bound to anthranilate phosphoribosyltransferase (AnPRT; trpD) in absence of substrates.
Structural highlights
FunctionPublication Abstract from PubMedThe 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 AlsoReferences
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