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Title | Cryo-EM structures of human fucosidase FucA1 reveal insight into substrate recognition and catalysis. |
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Journal, issue, pages | Structure, Vol. 30, Issue 10, Page 1443-11451.e5, Year 2022 |
Publish date | Oct 6, 2022 |
Authors | Zachary Armstrong / Richard W Meek / Liang Wu / James N Blaza / Gideon J Davies / |
PubMed Abstract | Enzymatic hydrolysis of α-L-fucose from fucosylated glycoconjugates is consequential in bacterial infections and the neurodegenerative lysosomal storage disorder fucosidosis. Understanding human α- ...Enzymatic hydrolysis of α-L-fucose from fucosylated glycoconjugates is consequential in bacterial infections and the neurodegenerative lysosomal storage disorder fucosidosis. Understanding human α-L-fucosidase catalysis, in an effort toward drug design, has been hindered by the absence of three-dimensional structural data for any animal fucosidase. Here, we have used cryoelectron microscopy (cryo-EM) to determine the structure of human lysosomal α-L-fucosidase (FucA1) in both an unliganded state and in complex with the inhibitor deoxyfuconojirimycin. These structures, determined at 2.49 Å resolution, reveal the homotetrameric structure of FucA1, the architecture of the catalytic center, and the location of both natural population variations and disease-causing mutations. Furthermore, this work has conclusively identified the hitherto contentious identity of the catalytic acid/base as aspartate-276, representing a shift from both the canonical glutamate acid/base residue and a previously proposed glutamate residue. These findings have furthered our understanding of how FucA1 functions in both health and disease. |
External links | Structure / PubMed:35907402 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.49 Å |
Structure data | EMDB-13499, PDB-7pls: EMDB-13520, PDB-7pm4: |
Chemicals | ChemComp-NAG: ChemComp-HOH: ChemComp-DFU: |
Source |
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Keywords | HYDROLASE / Fucosidase |