3K46: Crystal structure of full-length E. coli beta-glucuronidase

The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial beta-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 beta-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 beta-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.
PDB ID: 3K46Download
MMDB ID: 86212
PDB Deposition Date: 2009/10/5
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.5  Å
Source Organism:
Similar Structures:
Biological Unit for 3K46: tetrameric; determined by author and by software (PISA)
Molecular Components in 3K46
Label Count Molecule
Proteins (4 molecules)
Beta-glucuronidase(Gene symbol: uidA)
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB