{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T17:42:02Z","timestamp":1792431722491,"version":"4.5.0"},"reference-count":49,"publisher":"National Academy of Sciences","issue":"37","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,9,13]]},"abstract":"<jats:p>\n                    Krabbe disease is a devastating neurodegenerative disease characterized by widespread demyelination that is caused by defects in the enzyme galactocerebrosidase (GALC). Disease-causing mutations have been identified throughout the\n                    <jats:italic>GALC<\/jats:italic>\n                    gene. However, a molecular understanding of the effect of these mutations has been hampered by the lack of structural data for this enzyme. Here we present the crystal structures of GALC and the GALC-product complex, revealing a novel domain architecture with a previously uncharacterized lectin domain not observed in other hydrolases. All three domains of GALC contribute residues to the substrate-binding pocket, and disease-causing mutations are widely distributed throughout the protein. Our structures provide an essential insight into the diverse effects of pathogenic mutations on GALC function in human Krabbe variants and a compelling explanation for the severity of many mutations associated with fatal infantile disease. The localization of disease-associated mutations in the structure of GALC will facilitate identification of those patients that would be responsive to pharmacological chaperone therapies. Furthermore, our structure provides the atomic framework for the design of such drugs.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1105639108","type":"journal-article","created":{"date-parts":[[2011,8,29]],"date-time":"2011-08-29T22:04:21Z","timestamp":1314655461000},"page":"15169-15173","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":100,"title":["Insights into Krabbe disease from structures of galactocerebrosidase"],"prefix":"10.1073","volume":"108","author":[{"given":"Janet E.","family":"Deane","sequence":"first","affiliation":[{"name":"Department of Haematology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen C.","family":"Graham","sequence":"additional","affiliation":[{"name":"Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 0XY, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nee Na","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Penelope E.","family":"Stein","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosamund","family":"McNair","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Bego\u00f1a","family":"Cach\u00f3n-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy M.","family":"Cox","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Addenbrooke\u2019s Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randy J.","family":"Read","sequence":"additional","affiliation":[{"name":"Department of Haematology and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,8,29]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1177\/08830738030180090201","article-title":"Globoid cell leukodystrophy (Krabbe\u2019s disease): Update","volume":"18","author":"Suzuki K","year":"2003","unstructured":"K Suzuki, Globoid cell leukodystrophy (Krabbe\u2019s disease): Update. J Child Neurol 18, 595\u2013603 (2003).","journal-title":"J Child Neurol"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/0165-3806(86)90009-X","article-title":"The twitcher mouse: Degeneration of oligodendrocytes in vitro","volume":"391","author":"Nagara H","year":"1986","unstructured":"H Nagara, H Ogawa, Y Sato, T Kobayashi, K Suzuki, The twitcher mouse: Degeneration of oligodendrocytes in vitro. Brain Res 391, 79\u201384 (1986).","journal-title":"Brain Res"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/0006-8993(88)90835-9","article-title":"The twitcher mouse: Accumulation of galactosylsphingosine and pathology of the sciatic nerve","volume":"454","author":"Tanaka K","year":"1988","unstructured":"K Tanaka, H Nagara, T Kobayashi, I Goto, The twitcher mouse: Accumulation of galactosylsphingosine and pathology of the sciatic nerve. 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