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Chemical & Structural Biology of Protein Interfaces
Our research aims to elucidate phenomena related to biomolecular recognition and complexity in Chemical Biology and Structural Biology. Most proteins perform their cellular role as part of multi-subunit and multi-domain macromolecular complexes, and functional protein-protein interactions are often dictated by the post-translational modifications (PTMs) of specific amino acids. These further expand Nature's inventory of recognition patterns and regulatory mechanisms. We seek to understand the principles that determine specificity of molecular recognition at protein-protein interfaces and to exploit the druggability of interfaces by probing them with small molecules. We develop and apply the methods and concepts of fragment-based ligand design in order to dissect binding hot spots and structure-activity relationships. We ultimately aspire to translate this knowledge into cell-active small molecules that may serve as chemical probes of specific cellular processes, tools to validate the therapeutic potential of target proteins, and starting points for drug discovery.
We are presently carrying out studies in two areas:
- (a) Cullin-Ring Ligases (CRLs), the largest family of multi-subunit E3 ubiquitin ligases in eukaryotes. These enzymatic machines are responsible for the recognition, poly-ubiquitination and proteasome-dependent degradation of a wide range of protein substrates, thereby tightly regulating substrate cellular homeostasis. We are presently focusing on CRL complexes in which the substrate binding subunit is linked to the central Cullin scaffold subunit via the evolutionary conserved Elongin B/C adaptor. Several members of this family are attractive targets against cancer and other diseases.
- (b) Multi-domain readers of PTMs as epigenetic marks. We are focusing on bromodomains, a structurally conserved family of domains that read lysine acetylation on histone tails and other substrate proteins. Bromodomains, of which 57 are in the human genome, are often found in tandem with other domains e.g. PHD fingers to enable multiple readouts of PTMs during transcription and chromatin remodelling. Knowledge of the function of many proteins containing bromodomains is still lacking, yet recent data has implicated them in the development of a wide range of diseases.
Research in these areas involves multidisciplinary studies of protein-protein and protein-ligand interactions that combine the methods of Chemical & Structural Biology, including: protein expression, purification and engineering; structural and biophysical studies using protein X-ray crystallography, NMR and fluorescence spectroscopy, mass spectrometry and isothermal titration calorimetry; fragment screening and structure-based drug design; molecular modelling and dynamics; peptide and protein chemistry; synthesis and biological evaluation of chemical probes.
Dissecting fragment-based lead discovery at the von-Hippel Lindau protein : Hypoxia Inducible Factor 1α protein-protein interface, Chem. Biol. 19, 1300–1312 (2012)
Targeting the von Hippel–Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction, J. Am. Chem. Soc. 134, 4465–4468 (2012)
Bromodomain-peptide displacement assays for interactome mapping and inhibitor discovery, Mol. Biosyst. 7, 2899–2908 (2011)
Fragment-based approaches to enzyme inhibition, Curr. Opin. Biotechnol. 18, 489–496, (2007)
Probing hot spots at protein-ligand binding sites: a fragment-based approach using biophysical methods, J. Med. Chem. 49, 4992–5000, (2006)
For more detailed information please visit http://www-ciulli.ch.cam.ac.uk.
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