View source for 9sx4


==Human fumarylacetoacetate hydrolase (FAH) in complex with HT1.6==
<StructureSection load='9sx4' size='340' side='right'caption='[[9sx4]], [[Resolution|resolution]] 1.42&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9sx4]] 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=9SX4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9SX4 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]] 1.42&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JRB:2,5-dimethyl-1-(4-methylpyridin-2-yl)pyrrole-3-carbaldehyde'>A1JRB</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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=9sx4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9sx4 OCA], [https://pdbe.org/9sx4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9sx4 RCSB], [https://www.ebi.ac.uk/pdbsum/9sx4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9sx4 ProSAT]</span></td></tr>
</table>
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== Publication Abstract from PubMed ==
Hereditary tyrosinemia type 1 (HT1) stems from the loss of fumarylacetoacetate hydrolase (FAH) activity, causing severe liver-kidney disease. Nitisinone does not restore FAH function and carries metabolic and dietary burdens. Here, we used an integrated workflow guided by X-ray structures of human FAH to obtain small-molecule pharmacological chaperones that bind with low-muM affinity and stabilize FAH. Hits were validated by NMR and isothermal titration calorimetry. Protein stabilization was assessed by DOSY-NMR and circular dichroism; functional effects were tested in FAH activity assays, a CRISPR-engineered cellular model, and testing in an animal model of HT1. Compounds shifted the G337S pathological variant toward the active dimer and slowed unfolding/aggregation, resulting in dose-dependent enhancement of FAH activity and partial rescue of FAH homeostasis in cells and the liver tissue of a mouse model of HT1. These molecules support a therapeutic approach that could complement nitisinone in HT1.

Rational Design of Small-Molecule Stabilizers of Human Fumarylacetoacetate Hydrolase for the Treatment of Tyrosinemia Type I.,Scarin R, Rojas AL, Gil-Martinez J, Gomez-Galan M, Torres-Mozas A, Lopitz-Otsoa F, Fernandez-Ramos D, Jimenez-Oses G, Mato JM, Millet O J Med Chem. 2026 May 12. doi: 10.1021/acs.jmedchem.5c03489. PMID:42117404<ref>PMID:42117404</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9sx4" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Millet O]]
[[Category: Rojas AL]]
[[Category: Scarin R]]