View source for 7wjv


==Crystal structure of human liver FBPase complexed with an covalent inhibitor==
<StructureSection load='7wjv' size='340' side='right'caption='[[7wjv]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7wjv]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WJV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WJV 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]] 1.724&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AMP:ADENOSINE+MONOPHOSPHATE'>AMP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=LSA:1,2-BENZISOTHIAZOL-3(2H)-ONE+1,1-DIOXIDE'>LSA</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PMQ:BENZYLCARBAMIC+ACID'>PMQ</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=7wjv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wjv OCA], [https://pdbe.org/7wjv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wjv RCSB], [https://www.ebi.ac.uk/pdbsum/7wjv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wjv ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/F16P1_HUMAN F16P1_HUMAN] Defects in FBP1 are the cause of fructose-1,6-bisphosphatase deficiency (FBPD) [MIM:[https://omim.org/entry/229700 229700]. FBPD is inherited as an autosomal recessive disorder mainly in the liver and causes life-threatening episodes of hypoglycemia and metabolic acidosis (lactacidemia) in newborn infants or young children.<ref>PMID:9382095</ref> <ref>PMID:12126934</ref> 
== Function ==
[https://www.uniprot.org/uniprot/F16P1_HUMAN F16P1_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
With a resurgence of covalent drugs, there is an urgent need for the identification of new moieties capable of cysteine bond formation. Herein, we report on the N-acylamino saccharin moieties capable of novel covalent reactions with cysteine. Their utility as alternative electrophilic warheads was demonstrated through the covalent modification of fructose-1,6-bisphosphatase (FBPase), a promising target associated with cancer and type 2 diabetes. The cocrystal structure of title compound W8 bound with FBPase unexpectedly revealed that the N-acylamino saccharin moiety worked as an electrophile warhead that covalently modified the noncatalytic C128 site in FBPase while releasing saccharin, suggesting a previously undiscovered covalent reaction mechanism of saccharin derivatives with cysteine. Treatment of title compound W8 displayed potent inhibition of glucose production in vitro and in vivo. This newly discovered reactive warhead supplements the current repertoire of cysteine covalent modifiers while avoiding some of the limitations generally associated with established moieties.

N-Acylamino Saccharin as an Emerging Cysteine-Directed Covalent Warhead and Its Application in the Identification of Novel FBPase Inhibitors toward Glucose Reduction.,Wen W, Cao H, Xu Y, Ren Y, Rao L, Shao X, Chen H, Wu L, Liu J, Su C, Peng C, Huang Y, Wan J J Med Chem. 2022 Jul 14;65(13):9126-9143. doi: 10.1021/acs.jmedchem.2c00336. Epub , 2022 Jul 4. PMID:35786925<ref>PMID:35786925</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7wjv" style="background-color:#fffaf0;"></div>

==See Also==
*[[Fructose-1%2C6-bisphosphatase 3D structures|Fructose-1%2C6-bisphosphatase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cao H]]
[[Category: Huang Y]]
[[Category: Ren Y]]
[[Category: Wan J]]