View source for 9z2c


==KHK Bound to GS-1291269==
<StructureSection load='9z2c' size='340' side='right'caption='[[9z2c]], [[Resolution|resolution]] 2.02&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9z2c]] is a 2 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=9Z2C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9Z2C 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]] 2.02&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1C0H:3-[4-[7,7-bis(fluoranyl)-2-[(2~{R})-2-(trifluoromethyl)azetidin-1-yl]-5,6-dihydrocyclopenta[d]pyrimidin-4-yl]phenyl]-1,1-bis(oxidanylidene)thietan-3-amine'>A1C0H</scene>, <scene name='pdbligand=FRU:FRUCTOSE'>FRU</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=9z2c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9z2c OCA], [https://pdbe.org/9z2c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9z2c RCSB], [https://www.ebi.ac.uk/pdbsum/9z2c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9z2c ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/KHK_HUMAN KHK_HUMAN] Defects in KHK are the cause of fructosuria (FRUCT) [MIM:[https://omim.org/entry/229800 229800]. Benign defect of intermediary metabolism.<ref>PMID:19237742</ref> <ref>PMID:7833921</ref> 
== Function ==
[https://www.uniprot.org/uniprot/KHK_HUMAN KHK_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Ketohexokinase (KHK) is the primary enzyme involved in fructose metabolism, converting fructose to fructose-1-phosphate (F1P). KHK is implicated in diseases, including metabolic-dysfunction-associated steatotic liver disease (MASLD) and diabetic kidney disease (DKD), among others. Herein, we describe the discovery of GS-1291269, a potent, neutral KHK inhibitor. GS-1291269 has pharmacokinetic parameters in preclinical species that support once-daily dosing in humans. The high potency and favorable PK profile of GS-1291269 can be attributed to the uncommon dioxo-thietane amine functional group, which avoids potential PK liabilities associated with acidic or basic molecules yet provides a hydrogen bond donor that is critical for potency. Furthermore, GS-1291269 demonstrated liver and kidney fructose-1-phosphate (F1P) reduction in a fructose challenge model in rats.

The Discovery of GS-1291269: A Neutral Ketohexokinase (KHK) Inhibitor with an Unusual Thietane Amine Functional Group.,Kasun ZA, Liang X, Ferrao RD, Kaplan JA, Clark CT, Neubig ME, Byun DH, Badal SS, Sroda N, Mistry T, Stanley NH, Stevens KL, Bachman JL, Lo JR, Loyer-Drew J, Velasquez M, Hao J, Mwangi J, Stafford B, Jansa P J Med Chem. 2025 Dec 23. doi: 10.1021/acs.jmedchem.5c02896. PMID:41433313<ref>PMID:41433313</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9z2c" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Ferrao RD]]