{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T14:42:16Z","timestamp":1792680136072,"version":"4.5.0"},"reference-count":34,"publisher":"National Academy of Sciences","issue":"27","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,7,7]]},"abstract":"<jats:p>\n                    Muscle contraction and relaxation is regulated by transient elevations of myoplasmic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    . Ca\n                    <jats:sup>2+<\/jats:sup>\n                    is released from stores in the lumen of the sarco(endo)plasmic reticulum (SER) to initiate formation of the Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transient by activation of a class of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release channels referred to as ryanodine receptors (RyRs) and is pumped back into the SER lumen by Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -ATPases (SERCAs) to terminate the Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transient. Mutations in the type 1 ryanodine receptor gene,\n                    <jats:italic>RYR1<\/jats:italic>\n                    , are associated with 2 skeletal muscle disorders, malignant hyperthermia (MH), and central core disease (CCD). The evaluation of proposed mechanisms by which RyR1 mutations cause MH and CCD is hindered by the lack of high-resolution structural information. Here, we report the crystal structure of the N-terminal 210 residues of RyR1 (RyR\n                    <jats:sub>NTD<\/jats:sub>\n                    ) at 2.5 \u212b. The RyR\n                    <jats:sub>NTD<\/jats:sub>\n                    structure is similar to that of the suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor (IP\n                    <jats:sub>3<\/jats:sub>\n                    Rsup), but lacks most of the long helix-turn-helix segment of the \u201carm\u201d domain in IP\n                    <jats:sub>3<\/jats:sub>\n                    Rsup. The N-terminal \u03b2-trefoil fold, found in both RyR and IP\n                    <jats:sub>3<\/jats:sub>\n                    R, is likely to play a critical role in regulatory mechanisms in this channel family. A disease-associated mutation \u201chot spot\u201d loop was identified between strands 8 and 9 in a highly basic region of RyR1. Biophysical studies showed that 3 MH-associated mutations (C36R, R164C, and R178C) do not adversely affect the global stability or fold of RyR\n                    <jats:sub>NTD<\/jats:sub>\n                    , supporting previously described mechanisms whereby mutations perturb protein\u2013protein interactions.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0905186106","type":"journal-article","created":{"date-parts":[[2009,6,18]],"date-time":"2009-06-18T22:00:12Z","timestamp":1245362412000},"page":"11040-11044","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":84,"title":["Crystal structure of type I ryanodine receptor amino-terminal \u03b2-trefoil domain reveals a disease-associated mutation \u201chot spot\u201d loop"],"prefix":"10.1073","volume":"106","author":[{"given":"Fernando J.","family":"Amador","sequence":"first","affiliation":[{"name":"Division of Signaling Biology, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, Canada M5G 1L7; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Signaling Biology, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, Canada M5G 1L7; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noboru","family":"Ishiyama","sequence":"additional","affiliation":[{"name":"Division of Signaling Biology, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, Canada M5G 1L7; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Plevin","sequence":"additional","affiliation":[{"name":"Division of Signaling Biology, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, Canada M5G 1L7; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Wilson","sequence":"additional","affiliation":[{"name":"Banting and Best Department of Medical Research, University of Toronto, Charles H. Best Institute, 112 College Street, Toronto, ON, Canada MG5 IL6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"MacLennan","sequence":"additional","affiliation":[{"name":"Banting and Best Department of Medical Research, University of Toronto, Charles H. Best Institute, 112 College Street, Toronto, ON, Canada MG5 IL6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuhiko","family":"Ikura","sequence":"additional","affiliation":[{"name":"Division of Signaling Biology, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, Canada M5G 1L7; 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