7x67: Difference between revisions
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==Crystal structure of AtHPPD-Y18406 complex== | |||
<StructureSection load='7x67' size='340' side='right'caption='[[7x67]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7x67]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Arabidopsis_thaliana Arabidopsis thaliana]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7X67 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7X67 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.996Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9ZH:1,5-dimethyl-6-(2-oxidanyl-6-oxidanylidene-cyclohexen-1-yl)carbonyl-3-(3-phenylpropyl)quinazoline-2,4-dione'>9ZH</scene>, <scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene></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=7x67 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7x67 OCA], [https://pdbe.org/7x67 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7x67 RCSB], [https://www.ebi.ac.uk/pdbsum/7x67 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7x67 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/HPPD_ARATH HPPD_ARATH] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
High-potency 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors are usually featured by time-dependent inhibition. However, the molecular mechanism underlying time-dependent inhibition by HPPD inhibitors has not been fully elucidated. Here, based on the determination of the HPPD binding mode of natural products, the pi-pi sandwich stacking interaction was found to be a critical element determining time-dependent inhibition. This result implied that, for the time-dependent inhibitors, strengthening the pi-pi sandwich stacking interaction might improve their inhibitory efficacy. Consequently, modification with one methyl group on the bicyclic ring of quinazolindione inhibitors was achieved, thereby strengthening the stacking interaction and significantly improving the inhibitory efficacy. Further introduction of bulkier hydrophobic substituents with higher flexibility resulted in a series of HPPD inhibitors with outstanding subnanomolar potency. Exploration of the time-dependent inhibition mechanism and molecular design based on the exploration results are very successful cases of structure-based rational design and provide a guiding reference for future development of HPPD inhibitors. | |||
Discovery of Subnanomolar Inhibitors of 4-Hydroxyphenylpyruvate Dioxygenase via Structure-Based Rational Design.,Dong J, Dong J, Yu XH, Yan YC, Nan JX, Ye BQ, Yang WC, Lin HY, Yang GF J Agric Food Chem. 2023 Jan 18;71(2):1170-1177. doi: 10.1021/acs.jafc.2c06727. , Epub 2023 Jan 4. PMID:36599124<ref>PMID:36599124</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 7x67" style="background-color:#fffaf0;"></div> | ||
[[Category: Dong | |||
[[Category: Yang | ==See Also== | ||
*[[Dioxygenase 3D structures|Dioxygenase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Arabidopsis thaliana]] | |||
[[Category: Large Structures]] | |||
[[Category: Dong J]] | |||
[[Category: Lin H-Y]] | |||
[[Category: Yang G-F]] | |||
Latest revision as of 20:48, 29 November 2023
Crystal structure of AtHPPD-Y18406 complexCrystal structure of AtHPPD-Y18406 complex
Structural highlights
FunctionPublication Abstract from PubMedHigh-potency 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors are usually featured by time-dependent inhibition. However, the molecular mechanism underlying time-dependent inhibition by HPPD inhibitors has not been fully elucidated. Here, based on the determination of the HPPD binding mode of natural products, the pi-pi sandwich stacking interaction was found to be a critical element determining time-dependent inhibition. This result implied that, for the time-dependent inhibitors, strengthening the pi-pi sandwich stacking interaction might improve their inhibitory efficacy. Consequently, modification with one methyl group on the bicyclic ring of quinazolindione inhibitors was achieved, thereby strengthening the stacking interaction and significantly improving the inhibitory efficacy. Further introduction of bulkier hydrophobic substituents with higher flexibility resulted in a series of HPPD inhibitors with outstanding subnanomolar potency. Exploration of the time-dependent inhibition mechanism and molecular design based on the exploration results are very successful cases of structure-based rational design and provide a guiding reference for future development of HPPD inhibitors. Discovery of Subnanomolar Inhibitors of 4-Hydroxyphenylpyruvate Dioxygenase via Structure-Based Rational Design.,Dong J, Dong J, Yu XH, Yan YC, Nan JX, Ye BQ, Yang WC, Lin HY, Yang GF J Agric Food Chem. 2023 Jan 18;71(2):1170-1177. doi: 10.1021/acs.jafc.2c06727. , Epub 2023 Jan 4. PMID:36599124[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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