We are trying to develop a detailed structural understanding of the network of interacting pathways involved in phospholipid signalling.
Our current efforts focus on phosphoinositide 3-kinases and their downstream effectors. Due to their frequent mutation in human cancers and their roles in the immune systems, a structural understanding of class I PI3Ks is important for drug development.
Amongst many cellular processes regulated by specific phospholipid recognition are membrane protein sorting into multivesicular bodies (MVB) and autophagy, which are dependent on 3-phosphoinositides derived from class III PI3Ks.
We are determining the structures of endosomal and autophagosomal protein complexes.
In addition to X-ray crystallography, we are using electron microscopy, protein engineering, biophysical methods and in vivo assays to characterise these regulatory interactions.
- Zhang, X., Vadas, O., Perisic, O., Anderson, K.E., Clark, J., Hawkins, P.T., Stephens, L.R. and Williams, R.L. (2011)
Structure of lipid kinase p110β/p85 elucidates a novel SH2-domain mediated inhibitory mechanism.
Mol Cell 41: 567-578.
- Berndt, A., Miller, S., Williams, O., Le, D.D., Houseman, B.T., Pacold, J.I., Gorrec, F., Hon, W.C., Ren, P., Liu, Y., Rommel, C., Gaillard, P., Ruckle, T., Schwarz, M.K., Shokat, K.M., Shaw, J.P. and Williams, R.L. (2010)
The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.
Nat Chem Biol. 6: (2): 117-124.
- Miller S., Tavshanjian B., Oleksy A., Perisic O., Houseman B.T., Shokat K.M. and Williams R.L. (2010)
Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34.
Science 327: (5973):1638-1642.
- Samson, R.Y., Obita, T., Freund, S.M., Williams, R. L. and Bell, S.D. (2008)
A Role for the ESCRT System in Cell Division in Archaea.
Science 322: 1710-1713.
- Obita, T., Saksena, S., Ghazi-Tabatabai, S., Gill, D.J., Perisic, O., Emr, S. and Williams,R.L. (2007)
Structural basis for selective recognition of ESCRT-III by the AAA-ATPase Vps4.
Nature 449: 735-739.
- Olga Perisic
- Yohei Ohashi
- Alex Berndt
- Domagoj Baretic
- Glenn Masson
- Apostolos Apostolakis
- Ksenia Rostislavleva
- Alison Inglis