1R7T

Glycosyltransferase A in complex with 3-deoxy-acceptor analog inhibitor

Summary for 1R7T

• Entry DOI: 10.2210/pdb1r7t/pdb
• Related: 1R7U 1R7V 1R7X 1R7Y 1R80 1R81 1R82
• Descriptor: Glycoprotein-fucosylgalactoside alpha-N-acetylgalactosaminyltransferase, alpha-L-fucopyranose-(1-2)-hexyl 3-deoxy-beta-D-galactopyranoside, MERCURY (II) ION, ... (4 entities in total)
• Functional Keywords: glycoprotein, transmembrane, signal-anchor, blood group antigen, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Golgi apparatus, Golgi stack membrane; Single-pass type II membrane protein: P16442
• Total number of polymer chains: 1
• Total formula weight: 34195.97

Authors

Nguyen, H.P.,Seto, N.O.L.,Cai, Y.,Leinala, E.K.,Borisova, S.N.,Palcic, M.M.,Evans, S.V. (deposition date: 2003-10-22, release date: 2004-02-10, Last modification date: 2024-05-29)

Primary citation

Nguyen, H.P.,Seto, N.O.L.,Cai, Y.,Leinala, E.K.,Borisova, S.N.,Palcic, M.M.,Evans, S.V.
The influence of an intramolecular hydrogen bond in differential recognition of inhibitory acceptor analogs by human ABO(H) blood group A and B glycosyltransferases
J.Biol.Chem., 278:49191-49195, 2003

PubMed Abstract: Human ABO(H) blood group glycosyltransferases GTA and GTB catalyze the final monosaccharide addition in the biosynthesis of the human A and B blood group antigens. GTA and GTB utilize a common acceptor, the H antigen disaccharide alpha-l-Fucp-(1-->2)-beta-d-Galp-OR, but different donors, where GTA transfers GalNAc from UDP-GalNAc and GTB transfers Gal from UDP-Gal. GTA and GTB are two of the most homologous enzymes known to transfer different donors and differ in only 4 amino acid residues, but one in particular (Leu/Met-266) has been shown to dominate the selection between donor sugars. The structures of the A and B glycosyltransferases have been determined to high resolution in complex with two inhibitory acceptor analogs alpha-l-Fucp(1-->2)-beta-d-(3-deoxy)-Galp-OR and alpha-l-Fucp-(1-->2)-beta-d-(3-amino)-Galp-OR, in which the 3-hydroxyl moiety of the Gal ring has been replaced by hydrogen or an amino group, respectively. Remarkably, although the 3-deoxy inhibitor occupies the same conformation and position observed for the native H antigen in GTA and GTB, the 3-amino analog is recognized differently by the two enzymes. The 3-amino substitution introduces a novel intramolecular hydrogen bond between O2' on Fuc and N3' on Gal, which alters the minimum-energy conformation of the inhibitor. In the absence of UDP, the 3-amino analog can be accommodated by either GTA or GTB with the l-Fuc residue partially occupying the vacant UDP binding site. However, in the presence of UDP, the analog is forced to abandon the intramolecular hydrogen bond, and the l-Fuc residue is shifted to a less ordered conformation. Further, the residue Leu/Met-266 that was thought important only in distinguishing between donor substrates is observed to interact differently with the 3-amino acceptor analog in GTA and GTB. These observations explain why the 3-deoxy analog acts as a competitive inhibitor of the glycosyltransferase reaction, whereas the 3-amino analog displays complex modes of inhibition.

PubMed: 12972418
DOI: 10.1074/jbc.M308770200

Experimental method

X-RAY DIFFRACTION (2.09 Å)