Druggability of SCF ubiquitin ligase-protein interfaces.
The unique mechanism of the SCF ubiquitin ligase poses a challenge to drug discovery. A central enzymatic small molecule-binding active site is not evident in this multisubunit protein enzyme, as is the case with kinases or proteases. Instead, the SCF ligase seems to accomplish ubiquitylation through a series of cooperative movements dependent on the protein interfaces between its components and its substrate. Activity-modulating small molecules, therefore, need to interact with these protein interfaces. The three-dimensional structure of these interfaces may be the key asset in determining their suitability for small molecule binding. Computational tools and a systematic approach described in detail here can assess the "druggability" of an SCF ligase before the investment of effort in high-throughput screening (HTS), structure-based drug design (SBBD), or virtual library screening (VLS).
Cardozo
Timothy
T
Structural Chemistry Group, Hoffmann-La Roche, Inc., Nutley, New Jersey, USA.
Abagyan
Ruben
R
D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*
D008024:Ligands; D011506:Proteins; D044843:SKP Cullin F-Box Protein Ligases