{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T07:17:29Z","timestamp":1785827849093,"version":"3.56.0"},"reference-count":32,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2017,5,3]],"date-time":"2017-05-03T00:00:00Z","timestamp":1493769600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"The Wellcome Trust","doi-asserted-by":"crossref","award":["096919\/Z\/11\/Z (to Z.C.L.)"],"award-info":[{"award-number":["096919\/Z\/11\/Z (to Z.C.L.)"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mutations in the mitochondrial aminoacyl\u2010tRNA synthetases (<jats:italic>mt<\/jats:italic>aaRSs) can cause profound clinical presentations, and have manifested as diseases with very selective tissue specificity. To date most of the <jats:italic>mt<\/jats:italic>aaRS mutations could be phenotypically recognized, such that clinicians could identify the affected <jats:italic>mt<\/jats:italic>aaRS from the symptoms alone. Among the recently reported pathogenic variants are point mutations in <jats:italic>FARS2<\/jats:italic> gene, encoding the human mitochondrial PheRS. Patient symptoms range from spastic paraplegia to fatal infantile Alpers encephalopathy. How clinical manifestations of these mutations relate to the changes in three\u2010dimensional structures and kinetic characteristics remains unclear, although impaired aminoacylation has been proposed as possible etiology of diseases. Here, we report four crystal structures of <jats:italic>Hsmt<\/jats:italic>PheRS mutants, and extensive MD simulations for wild\u2010type and nine mutants to reveal the structural changes on dynamic trajectories of <jats:italic>Hsmt<\/jats:italic>PheRS. Using steady\u2010state kinetic measurements of phenylalanine activation and tRNA<jats:sup>Phe<\/jats:sup> aminoacylation, we gained insight into the structural and kinetic effects of mitochondrial disease\u2010related mutations in <jats:italic>FARS2<\/jats:italic> gene.<\/jats:p>","DOI":"10.1002\/pro.3176","type":"journal-article","created":{"date-parts":[[2017,4,17]],"date-time":"2017-04-17T15:32:47Z","timestamp":1492443167000},"page":"1505-1516","source":"Crossref","is-referenced-by-count":15,"title":["Kinetic and structural changes in <scp><i>H<\/i><\/scp><i>smt<\/i><scp>P<\/scp>he<scp>RS<\/scp>, induced by pathogenic mutations in human <scp><i>FARS<\/i><\/scp><i>2<\/i>"],"prefix":"10.1002","volume":"26","author":[{"given":"Ekaterine","family":"Kartvelishvili","sequence":"first","affiliation":[{"name":"Department of Structural Biology Weizmann Institute of Science  Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry","family":"Tworowski","sequence":"additional","affiliation":[{"name":"Department of Structural Biology Weizmann Institute of Science  Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary","family":"Vernon","sequence":"additional","affiliation":[{"name":"McKusick\u2010Nathans Institute of Genetic Medicine Johns Hopkins School of Medicine Baltimore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Moor","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic Chemistry of Enzymes Institute of Chemical Biology and Fundamental Medicine Novosibirsk Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Ambry Genetics  California"},{"name":"Molecular and Human Genetics, Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee\u2010Jun","family":"Wong","sequence":"additional","affiliation":[{"name":"Molecular and Human Genetics, Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zofia","family":"Chrzanowska\u2010Lightowlers","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Newcastle University Newcastle NE2 4HH United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Safro","sequence":"additional","affiliation":[{"name":"Department of Structural Biology Weizmann Institute of Science  Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,5,3]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/787956"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201100626"},{"key":"e_1_2_7_4_1","first-page":"352","article-title":"Novel pathogenic variants in the mitochondrial aminoacyl TRNA synthetases genes","volume":"114","author":"Wang J","year":"2015","journal-title":"Mol Genet Metab"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36993"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds294"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2013.10.008"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22930"},{"key":"e_1_2_7_9_1","first-page":"328","volume-title":"The aminoacyl\u2010tRNA synthetases","author":"First 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