3K4D

Crystal structure of E. coli beta-glucuronidase with the glucaro-d-lactam inhibitor bound

Summary for 3K4D

• Entry DOI: 10.2210/pdb3k4d/pdb
• Related: 3K46 3K4A
• Descriptor: Beta-glucuronidase, (2S,3R,4S,5R)-3,4,5-trihydroxy-6-oxopiperidine-2-carboxylic acid (3 entities in total)
• Functional Keywords: alpha/beta barrel, sugar-binding domain, beta-sandwich domain, glycosyl hydrolase, glucaro-d-lactam, glycosidase, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 137876.18

Authors

Wallace, B.D.,Redinbo, M.R. (deposition date: 2009-10-05, release date: 2010-11-17, Last modification date: 2023-09-06)

Primary citation

Wallace, B.D.,Wang, H.,Lane, K.T.,Scott, J.E.,Orans, J.,Koo, J.S.,Venkatesh, M.,Jobin, C.,Yeh, L.A.,Mani, S.,Redinbo, M.R.
Alleviating cancer drug toxicity by inhibiting a bacterial enzyme.
Science, 330:831-835, 2010

PubMed Abstract: The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial β-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial β-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial β-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11-induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy.

PubMed: 21051639
DOI: 10.1126/science.1191175

Experimental method

X-RAY DIFFRACTION (2.393 Å)