2O6L

Crystal Structure of the UDP-Glucuronic Acid Binding Domain of the Human Drug Metabolizing UDP-Glucuronosyltransferase 2B7

Summary for 2O6L

• Entry DOI: 10.2210/pdb2o6l/pdb
• Descriptor: UDP-glucuronosyltransferase 2B7 (2 entities in total)
• Functional Keywords: drug metabolism, rossman, mad, enzyme, nucleotide binding, sugar, udp-glucuronosyltransferase, ugt, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Microsome membrane; Single-pass membrane protein (Potential): P16662
• Total number of polymer chains: 2
• Total formula weight: 38251.44

Authors

Miley, M.J.,Redinbo, M.R. (deposition date: 2006-12-07, release date: 2007-05-01, Last modification date: 2024-10-30)

Primary citation

Miley, M.J.,Zielinska, A.K.,Keenan, J.E.,Bratton, S.M.,Radominska-Pandya, A.,Redinbo, M.R.
Crystal Structure of the Cofactor-Binding Domain of the Human Phase II Drug-Metabolism Enzyme UDP-Glucuronosyltransferase 2B7.
J.Mol.Biol., 369:498-511, 2007

PubMed Abstract: Human UDP-glucuronosyltransferases (UGT) are the dominant phase II conjugative drug metabolism enzymes that also play a central role in processing a range of endobiotic compounds. UGTs catalyze the covalent addition of glucuronic acid sugar moieties to a host of therapeutics and environmental toxins, as well as to a variety of endogenous steroids and other signaling molecules. We report the 1.8-A resolution apo crystal structure of the UDP-glucuronic acid binding domain of human UGT isoform 2B7 (UGT2B7), which catalyzes the conjugative elimination of opioid, antiviral, and anticancer drugs. This is the first crystal structure of any region of a mammalian UGT drug metabolism enzyme. Designated UGT2B7 mutants at residues predicted to interact with the UDP-glucuronic acid cofactor exhibited significantly impaired catalytic activity, with maximum effects observed for amino acids closest to the glucuronic acid sugar transferred to the acceptor molecule. Homology modeling of UGT2B7 with related plant flavonoid glucosyltransferases indicates human UGTs share a common catalytic mechanism. Point mutations at predicted catalytic residues in UGT2B7 abrogated activity, strongly suggesting human UGTs also utilize a serine hydrolase-like catalytic mechanism to facilitate glucuronic acid transfer.

PubMed: 17442341
DOI: 10.1016/j.jmb.2007.03.066

Experimental method

X-RAY DIFFRACTION (1.8 Å)