{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T20:24:35Z","timestamp":1785183875549,"version":"3.55.0"},"reference-count":49,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2020,3,18]],"date-time":"2020-03-18T00:00:00Z","timestamp":1584489600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["[203105\/Z\/16\/Z]"],"award-info":[{"award-number":["[203105\/Z\/16\/Z]"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:sec><jats:label\/><jats:p>Various pathogenic variants in both mitochondrial tRNA<jats:sup>Phe<\/jats:sup> and Phenylalanyl\u2010tRNA synthetase mitochondrial protein coding gene (FARS2) gene encoding for the human mitochondrial PheRS have been identified and associated with neurological and\/or muscle\u2010related pathologies. An important Guanine\u201034 (G34)A anticodon mutation associated with myoclonic epilepsy with ragged red fibers (MERRF) syndrome has been reported in <jats:italic>hmit<\/jats:italic>\u2010tRNA<jats:sup>Phe<\/jats:sup>. The majority of G34 contacts in available aaRSs\u2010tRNAs complexes specifically use that base as an important tRNA identity element. The network of intermolecular interactions providing its specific recognition also largely conserved. However, their conservation depends also on the invariance of the residues in the anticodon binding domain (ABD) of human mitochondrial Phenylalanyl\u2010tRNA synthetase (<jats:italic>hmit<\/jats:italic>\u2010PheRS). A defect in recognition of the anticodon of tRNA<jats:sup>Phe<\/jats:sup> may happen not only because of G34A mutation, but also due to mutations in the ABD. Indeed, a pathogenic mutation in FARS2 has been recently reported in a 9\u2010year\u2010old female patient harboring a p.Asp364Gly mutation. Asp364 is hydrogen bonded (HB) to G34 in WT <jats:italic>hmit<\/jats:italic>\u2010PheRS. Thus, there are two pathogenic variants disrupting HB between G34 and Asp364: one is associated with G34A mutation, and the other with Asp364Gly mutation. We have measured the rates of tRNA<jats:sup>Phe<\/jats:sup> aminoacylation catalyzed by WT <jats:italic>hmit<\/jats:italic>\u2010PheRS and mutant enzymes. These data ranked the residues making a HB with G34 according to their contribution to activity and the signal transduction pathway in the <jats:italic>hmit<\/jats:italic>\u2010PheRS\u2010tRNA<jats:sup>Phe<\/jats:sup> complex. Furthermore, we carried out extensive MD simulations to reveal the interdomain contact topology on the dynamic trajectories of the complex, and gaining insight into the structural and dynamic integrity effects of <jats:italic>hmit<\/jats:italic>\u2010PheRS complexed with tRNA<jats:sup>Phe<\/jats:sup>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Database<\/jats:title><jats:p>Structural data are available in PDB database under the accession number(s): <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.rcsb.org\/pdb\/search\/structidSearch.do?structureId=3CMQ\">3CMQ<\/jats:ext-link>, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.rcsb.org\/pdb\/search\/structidSearch.do?structureId=3TUP\">3TUP<\/jats:ext-link>, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.rcsb.org\/pdb\/search\/structidSearch.do?structureId=5MGH\">5MGH<\/jats:ext-link>, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.rcsb.org\/pdb\/search\/structidSearch.do?structureId=5MGV\">5MGV<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/febs.15268","type":"journal-article","created":{"date-parts":[[2020,3,2]],"date-time":"2020-03-02T08:00:00Z","timestamp":1583136000000},"page":"3814-3826","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Breaking a single hydrogen bond in the mitochondrial tRNA<sup>Phe<\/sup>\u2010PheRS complex leads to phenotypic pleiotropy of human disease"],"prefix":"10.1111","volume":"287","author":[{"given":"Moshe","family":"Peretz","sequence":"first","affiliation":[{"name":"Department of Structural Biology Weizmann Institute of Science Rehovot Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry","family":"Tworowski","sequence":"additional","affiliation":[{"name":"Department of Structural Biology Weizmann 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