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3hg2
From Proteopedia
| 3hg2, resolution 2.30Å () | |||||||||
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| Sites: | , , , , , , , , , , , , , , , , and | ||||||||
| Ligands: | , , , , , | ||||||||
| Gene: | GLA (Homo sapiens) | ||||||||
| Activity: | Alpha-galactosidase, with EC number 3.2.1.22 | ||||||||
| Related: | 3hg3, 3hg4, 3hg5, 1r46, 1r47 | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
Human alpha-galactosidase catalytic mechanism 1. Empty active site
The enzyme alpha-galactosidase (alpha-GAL, also known as alpha-GAL A; E.C. 3.2.1.22) is responsible for the breakdown of alpha-galactosides in the lysosome. Defects in human alpha-GAL lead to the development of Fabry disease, a lysosomal storage disorder characterized by the buildup of alpha-galactosylated substrates in the tissues. alpha-GAL is an active target of clinical research: there are currently two treatment options for Fabry disease, recombinant enzyme replacement therapy (approved in the United States in 2003) and pharmacological chaperone therapy (currently in clinical trials). Previously, we have reported the structure of human alpha-GAL, which revealed the overall structure of the enzyme and established the locations of hundreds of mutations that lead to the development of Fabry disease. Here, we describe the catalytic mechanism of the enzyme derived from x-ray crystal structures of each of the four stages of the double displacement reaction mechanism. Use of a difluoro-alpha-galactopyranoside allowed trapping of a covalent intermediate. The ensemble of structures reveals distortion of the ligand into a (1)S(3) skew (or twist) boat conformation in the middle of the reaction cycle. The high resolution structures of each step in the catalytic cycle will allow for improved drug design efforts on alpha-GAL and other glycoside hydrolase family 27 enzymes by developing ligands that specifically target different states of the catalytic cycle. Additionally, the structures revealed a second ligand-binding site suitable for targeting by novel pharmacological chaperones.
Catalytic mechanism of human alpha-galactosidase., Guce AI, Clark NE, Salgado EN, Ivanen DR, Kulminskaya AA, Brumer H 3rd, Garman SC, J Biol Chem. 2010 Feb 5;285(6):3625-32. Epub 2009 Nov 25. PMID:19940122
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Disease
Known disease associated with this structure: Fabry disease OMIM:[300644], Fabry disease, cardiac variant OMIM:[300644]
About this Structure
3HG2 is a 2 chains structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
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Original page seeded by OCA on Wed Nov 25 10:15:00 2009
