University of Dundee

Professor Alessio Ciulli FRSC

Chemical and Structural Biology of Protein-Protein Interactions
Position: 
Professor of Chemical and Structural Biology
Address: 
School of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 386230, int ext 86230
Email: 

Research

Research in the Ciulli Lab broadly spans the fields of Chemical Biology and Structural Biology of Protein-Protein Interactions (PPIs) and is specifically concerned with studies of druggability of PPIs to small molecule modulators. Of particular interest are protein surfaces and interfaces recognizing protein Post-Translational Modifications (PTMs) within multi-domain and multi-subunit protein complexes. We employ a question-driven, multi-disciplinary approach that combines chemical, biophysical and structural techniques with the concepts and approaches of fragment-based and structure-based drug design. The 'chemical probes' we design and develop are evaluated biophysically, structurally and whenever possible within living cells as tools to address biological questions, and as starting leads with potential to be developed as novel therapeutics.

Current and future research efforts are directed towards targeting PPIs and PTM recognition within two protein families of biological and medical relevance:

Ubiquitin System: the Cullin RING E3 ubiquitin ligases (CRLs) multisubunit complexes

Chromatin System: Multidomain proteins of containing paired domains of the epigenetic reader families

Teaching

BS42011:  A 4th year mocule entitled "Advanced Organic Chemistry and Chemical Biology"

Publications

1. A. C. Runcie, M. Zengerle, K.-H. Chan, A. Testa, L. van Beurden, M. G. J. Baud, O. Epemolu, L. C. J. Ellis, K. D. Read, V. Coulthard, A. Brien, A. Ciulli* Optimization of a “Bump-and-Hole” Approach to Allele-Selective BET Bromodomain Inhibition. Chem. Sci., 2018, 9, 2452–2468. (Read Online)

2. Maniaci, C., Hughes, S.J., Testa, A., Rocha, S., Alessi, D.R., Romeo, R., Ciulli, A.* Homo­PROTACs: bivalent small­molecule dimerizers of the VHL E3 ubiquitin ligase to induce self­degradation. Nat. Commun. 2017 8, 830. (Read Online)

3. Cardote, T.A.F., Gadd, M.S., Ciulli, A.* Crystal structure of the Cul2-Rbx1-EloBC-VHL ubiquitin ligase complex. Structure 2017, 25, 901–911. (Read Online)

4. Gadd, M.S., Testa, A., Lucas, X., Chan, K.-H., Chen, W., Lamont, D.J., Zengerle, M., Ciulli, A.* Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol. 2017, 13(5), 514–521. (Read Online)

5. Frost, J., Galdeano, C., Soares, P., Gadd, M.S., Grzes, K.M., Ellis, L., Epemolu, O., Shimamura, S., Bantscheff, M., Grandi, P., Read, K.D., Cantrell, D.A., Rocha, S., Ciulli, A.* Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition. Nat. Commun. 2016, 7, 13312. (Read Online)

6. Zengerle, M., Chan, K.-H., Ciulli, A.* Selective small molecules induced degradation of the BET bromodomain protein BRD4. ACS Chem. Biol. 2015, 10(8), 1770–1777 (Read Online)

7. Baud, M.G.J., Lin-Shiao, E., Cardote, T., Tallant, C., Pschibul, A., Chan, K.-H., Zengerle, M., Garcia, J.R., Kwan, T.T.-L., Ferguson, F.M., Ciulli, A.* A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes. Science, 2014, 346, 638–641. (Read Online)

8. Galdeano, C., Gadd, M., Soares, P., Scaffidi, S., Van Molle, I., Birced, I., Hewitt, S., Dias, D.M., Ciulli, A.* Structure-Guided Design and Optimization of Small Molecules Targeting the VHL E3 Ubiquitin Ligase and Disrupting its Interaction with HIF-1a with Nanomolar Affinities. J. Med. Chem., 2014, 57(20), 8657–8663. (Read Online)

9. Silvestre, H.L., Blundell, T.L., Abell, C., Ciulli, A.*  Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery. Proc. Natl. Acad. Sci. Usa, 2013, 110, 12984–12989 (Read Online)

10. Van Molle, I., Thomann, A., Buckley, D.L., So, E.C., Lang, S., Crews, C.M., Ciulli, A.* Dissecting fragment-based lead discovery at the von Hippel-Lindau protein:Hypoxia Inducible Factor 1a protein-protein interface. Chem. Biol. 2012, 19, 1300–1312. (Read Online)