8how: Difference between revisions
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==Crystal structure of AtHPPD-Y191052 complex== | |||
<StructureSection load='8how' size='340' side='right'caption='[[8how]], [[Resolution|resolution]] 1.79Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8how]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Arabidopsis_thaliana Arabidopsis thaliana]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=7x65 7x65]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8HOW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8HOW FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9YI:1,5-dimethyl-6-(2-oxidanyl-6-oxidanylidene-cyclohexen-1-yl)carbonyl-3-(2-phenylethyl)quinazoline-2,4-dione'>9YI</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=8how FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8how OCA], [https://pdbe.org/8how PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8how RCSB], [https://www.ebi.ac.uk/pdbsum/8how PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8how 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 8how" style="background-color:#fffaf0;"></div> | ||
[[Category: Lin | |||
[[Category: | ==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 15:12, 1 February 2023
Crystal structure of AtHPPD-Y191052 complexCrystal structure of AtHPPD-Y191052 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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