View source for 8p8x


==Crystal structure of a pathogenic mutant variant of human mitochodnrial PheRS==
<StructureSection load='8p8x' size='340' side='right'caption='[[8p8x]], [[Resolution|resolution]] 1.46&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8p8x]] is a 1 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=8P8X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8P8X 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]] 1.46&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PHE:PHENYLALANINE'>PHE</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=8p8x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8p8x OCA], [https://pdbe.org/8p8x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8p8x RCSB], [https://www.ebi.ac.uk/pdbsum/8p8x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8p8x ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/SYFM_HUMAN SYFM_HUMAN] Catalyzes direct attachment of p-Tyr (Tyr) to tRNAPhe. Permits also, with a lower efficiency, the attachment of m-Tyr to tRNAPhe, thereby opening the way for delivery of the misacylated tRNA to the ribosome and incorporation of ROS-damaged amino acid into proteins.<ref>PMID:19549855</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
FARS2 encodes the mitochondrial phenylalanyl-tRNA synthetase (mtPheRS), which is essential for charging mitochondrial (mt-) tRNA(Phe) with phenylalanine for use in intramitochondrial translation. Many biallelic, pathogenic FARS2 variants have been described previously, which are mostly associated with two distinct clinical phenotypes; an early onset epileptic mitochondrial encephalomyopathy or a later onset spastic paraplegia. In this study, we report on a patient who presented at 3 weeks of age with tachypnoea and poor feeding, which progressed to severe metabolic decompensation with lactic acidosis and seizure activity followed by death at 9 weeks of age. Rapid trio whole exome sequencing identified compound heterozygous FARS2 variants including a pathogenic exon 2 deletion on one allele and a rare missense variant (c.593G &gt; T, p.(Arg198Leu)) on the other allele, necessitating further work to aid variant classification. Assessment of patient fibroblasts demonstrated severely decreased steady-state levels of mtPheRS, but no obvious defect in any components of the oxidative phosphorylation system. To investigate the potential pathogenicity of the missense variant, we determined its high-resolution crystal structure, demonstrating a local structural destabilization in the catalytic domain. Moreover, the R198L mutation reduced the thermal stability and impaired the enzymatic activity of mtPheRS due to a lower binding affinity for tRNA(Phe) and a slower turnover rate. Together these data confirm the pathogenicity of this FARS2 variant in causing early-onset mitochondrial epilepsy.

Clinical and molecular characterization of novel FARS2 variants causing neonatal mitochondrial disease.,Chen W, Rehsi P, Thompson K, Yeo M, Stals K, He L, Schimmel P, Chrzanowska-Lightowlers ZMA, Wakeling E, Taylor RW, Kuhle B Mol Genet Metab. 2023 Jul 24;140(3):107657. doi: 10.1016/j.ymgme.2023.107657. PMID:37523899<ref>PMID:37523899</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8p8x" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chen W]]
[[Category: Kuhle B]]