Results tagged “science” from The SIBYLS Beamline

In the September 19, 2008 issue of Cell, we report striking conformational rearrangements in the crystal structure of NEDD8~Cul5ctd-Rbx1 and SAXS analysis of NEDD8~Cul1ctd-Rbx1 relative to their unmodified counterparts. These results point to conformational control of Cullin-RING ligase (CRL) activity, with ligation of NEDD8 shifting equilibria to disfavor inactive closed architectures, and favor dynamic, open forms that promote polyubiquitination.

Cullin-RING ligases (CRLs) comprise the largest ubiquitin E3 subclass, in which a central cullin subunit links a substrate-binding adaptor with an E2-binding RING. Covalent attachment of the ubiquitin-like protein NEDD8 to a conserved C-terminal domain (ctd) lysine stimulates CRL ubiquitination activity and prevents binding of the inhibitor CAND1. Here we report striking conformational rearrangements in the crystal structure of NEDD8~Cul5ctd-Rbx1 and SAXS analysis of NEDD8~Cul1ctd-Rbx1 relative to their unmodified counterparts. In NEDD8ylated CRL structures, the cullin WHB and Rbx1 RING subdomains are dramatically reoriented, eliminating a CAND1-binding site and imparting multiple potential catalytic geometries to an associated E2. Biochemical analyses indicate that the structural malleability is important for both CRL NEDD8ylation and subsequent ubiquitination activities. Thus, our results point to a conformational control of CRL activity, with ligation of NEDD8 shifting equilibria to disfavor inactive CAND1-bound closed architectures, and favor dynamic, open forms that promote polyubiquitination.

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The structure of Sulfolobus acidocaldarius XPD has recently been solved and the biochemical activites of various disease causing mutations measured. Results are reported in the May 30th issue of Cell. LBNL has also done a nice write up.

As recently reported in the ALSNews:

“The veil has finally been lifted on an enzyme that is critical to the process of DNA transcription and replication and is a prime target of antibacterial and anticancer drugs. Researchers at Berkeley Lab and the University of California, Berkeley, have produced the first three-dimensional structural images of a DNA-bound type II topoisomerase (topo II) that is responsible for untangling coiled strands of the chromosome during cell division. Preventing topo II from disentangling a cell’s DNA is fatal to the cell, which is why drugs that target topo II serve as agents against bacterial infections and some forms of cancer. This first ever structural image of topo II should help in the development of future antibacterial and anticancer drugs that are even more effective and carry fewer potential side effects.”

The original publication in Nature can be found here: K.C. Dong and J.M. Berger, “Structural basis for Gate-DNA recognition and bending by type IIA topoisomerases,” Nature 250, 1201 (2007).

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