3ZR6

STRUCTURE OF GALACTOCEREBROSIDASE FROM MOUSE IN COMPLEX WITH GALACTOSE

Summary for 3ZR6

• Entry DOI: 10.2210/pdb3zr6/pdb
• Related: 3ZR5
• Descriptor: GALACTOCEREBROSIDASE, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: hydrolase, galc, glycosyl hydrolase, krabbe disease, tim barrel, lectin domain
• Biological source: MUS MUSCULUS (MOUSE)
• Total number of polymer chains: 1
• Total formula weight: 76421.50

Authors

Deane, J.E.,Graham, S.C.,Kim, N.N.,Stein, P.E.,Mcnair, R.,Cachon-Gonzalez, M.B.,Cox, T.M.,Read, R.J. (deposition date: 2011-06-14, release date: 2011-09-28, Last modification date: 2024-11-13)

Primary citation

Deane, J.E.,Graham, S.C.,Kim, N.N.,Stein, P.E.,Mcnair, R.,Cachon-Gonzalez, M.B.,Cox, T.M.,Read, R.J.
Insights Into Krabbe Disease from Structures of Galactocerebrosidase.
Proc.Natl.Acad.Sci.USA, 108:15169-, 2011

PubMed Abstract: 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 GALC 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.

PubMed: 21876145
DOI: 10.1073/PNAS.1105639108

Experimental method

X-RAY DIFFRACTION (2.44 Å)