Tom has researched on architecture of macromolecules and multi-component assemblies , with focus on defining structures of complex biological molecules & relation of structure to biological function, knowledge-based prediction of structure & discovery of new therapeutics for cancer and tuberculosis, leprosy and cystic fibrosis.
Tom worked with Nobel Laureate Dorothy Hodgkin on the first structure of a protein hormone, insulin, and was involved in computational design of long lasting insulins. He has made major breakthroughs on the structural and computational biology and biophysics of hormones and growth factors (insulin, glucagon, NGF, HGF, FGF), receptor activation, signal transduction and DNA repair, important in cancer, tuberculosis and familial diseases.
He has produced many widely used software packages for protein modelling and design, including Modeller (~11,200 citations) and Fugue (~1200 citations), and for predicting effects of mutations on protein stability and interactions, e.g, SDM (statistical method) & mCSM(machine learning), to understand cancer & drug resistance.
Tom has developed new approaches to structure-guided and fragment-based drug discovery. In 1999 he co-founded Astex Therapeutics, an oncology company that has two cancer drugs on the market and five in clinical trials, sold in 2013 to Otsuka for $886 million.
In the University of Cambridge he developed structure-guided fragment-based approaches to drug discovery for difficult targets involving multiprotein systems and protein-protein interactions. He has targeted mycobacteria as part of Gates HIT-TB, American Leprosy Mission and Cystic Fibrosis Trust programmes, including studies of resistance mutations to first-line drugs.
The Blundell Group
The Blundell Group focuses on structural and computational biology and their applications to drug discovery. The experimental research seeks to understand multicomponent cell-regulatory systems, currently DNA repair through non-homologous end joining. The Group, which has defined the structure of the 4000-amino-acid kinase DNA-PKcs and discovered an important new component PAXX, is currently investigating their interactions using cryo-EM. The Blundell Group has also produced widely used software packages, including Modeller (~11,200 citations) and Fugue (~1,400 citations) for protein modelling, and SDM and mCSM for predicting effects of mutations on protein stability and interactions. The Group now focuses on machine learning as well as databases to underpin drug discovery and to understand cancer and drug resistance. Blundell has developed new approaches to structure-guided and fragment-based drug discovery in Astex Therapeutics, now with breast cancer and urothelial carcinoma drugs on market. In academia, he has targeted Mycobacterium tuberculosis proteins in the Gates HIT-TB consortium, M. leprae for the American Leprosy Mission and M. abscessus for the Cystic Fibrosis Trust.
Publications, Links, and Resources
Tom has published ~630 research papers, including ~40 in Nature and Science, and has an H-factor of 115.
First structures of polypeptide hormone and hypotheses re receptor binding: Adams et al. (1969) Structure of 2-Zinc insulin crystals Nature 224, 491-495; Blundell TL et al. (1971) Atomic positions in 2-Zinc insulin. Nature 231, 506-511; Pullen RA et al. (1976) Receptor-binding of insulin Nature 259, 369-373; Blundell TL & Wood SP (1975) Is evolution of insulin Darwinian or due to selectively neutral mutation? Nature 257, 197-203; Blundell TL & Humbel RE (1980) Hormone families Nature 287, 781-787; 506; Sasaki et al. (1975) X-ray analysis of glucagon and receptor binding Nature 257, 751-757; Wood SP et al (1986) Deamino-oxytocin: flexibility & receptor binding. Science 232, 633-636
Growth factors and receptor interactions: NGF, HGF/SF and FGF. McDonald et al (1991) Structure nerve growth factor. Nature 345: 411-414; Pellegrini et al. (2000) Crystal Structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin. Nature 407, 1029-1034 8. Chirgadze (1999). Structure of NK1 fragment of HGF/SF suggests novel mode for growth factor dimerization and receptor binding. Nature Struct. Biol. 6, 72-79. Brotherton et al.(1998) Crystal structure of the complex of the cyclin D-dependent kinase Cdk6 bound to the cell cycle inhibitor p19INK4d. Nature 395, 244-250
DNA Repair: homologous recombination and non-homologous end joining: Pellegrini et al (2002) Insights into DNA recombination from structure of RAD51-BRCA2 complex. Nature 420, 287-293; Sibanda et al (2001) DNA end joining from structure Xrcc4 dimer complex DNA ligase IV. Nature Struct. Biology 8, 1015-1019; Sibanda BL et al. (2010) Structure of DNA-PKcs Reveals a Large Open-Ring Cradle. Nature 463:118-21; Sibanda et al. (2017) Science.
Vertebrate lens: origins of transparency and cataract: Blundell TL et al. (1981) Structure and stability of the eye lens: X-ray analysis of gamma-crystallin II Nature 289, 771-777. 14. Slingsby et al. (1984) B-crystallin polypeptide in murine lens: relationship of exons and structural motifs. Nature 302, 310-315. Bax B. et al. (1990) bB2-crystallin and evolution of oligomeric lens proteins. Nature: 347, 776-780
Early approaches to structure-guided drug discovery: Renin and HIV proteinase: Sibanda BL et al (1983) Structure, specificity and catalytic mechanism of renin. Nature 304, 273-275; Tang et al (1978) Gene duplication in the evolution of acid proteinases Nature 271, 618-621; Lapatto R et al. (1989) X-ray analysis of HIV-1 proteinase at 2.7A resolution Nature 342, 299-302; Foundling SI et al. (1987) High resolution X-ray analyses of renin inhibitor-aspartic proteinase complexes Nature, 327, 349-352 Dhanaraj et al (1992) X-ray analyses of peptide inhibitor complexes Nature 357:466-472
Protein modelling and homology recognition: Sibanda et al. (1987) Knowledge-based prediction of protein structures and design of novel molecules Nature, 326, 347-352; Sali A & Blundell TL. (1993) Comparative modelling by satisfaction of spatial restraints. J. Mol. Biol. 234: 779-815 (over 10500 citations); Shi J et al. (2001) FUGUE: Sequence-structure Homology Recognition Using Environment-specific Substitution Tables and Structure-dependent Gap Penalties. J. Mol. Biol. 310, 243-257 (over 1200 citations).
Databases of protein interactions and drug discovery: Worth et al. (2009) Structure & function in evolution of protein families. Nature Rev Mol Cell Biol. 2009 10:709-20; Higueruelo A et al. (2009) Profile of Small Molecules Disrupting Protein-Protein Interfaces: the TIMBAL Database. Chem. Biol. Drug Des. 74, 457 – 467; Schreyer, A. & Blundell (2009) Credo: Protein-ligand database for drug discovery. Chem Biol Drug Des 73:157–167
Structure-guided Drug Discovery: Development of structure-guided drug discovery using X-ray crystal structures in 80s and 90s (renin and HIV proteinase, review: Blundell TL (1996). Structure-based drug design. Nature. 384S: 23-26.). Focus on fragment-based screening using X-ray analysis, initially in Astex 1999 (Blundell et al. (2002). High-throughput crystallography for drug design. Nature Reviews Drug Discovery. 1, 45-54. Congreve M et al (2005) Struct. Biol. Drug Discovery. Drug Discovery Today 10, 895-907) and then back in academia for difficult targets involving TB antimicrobials and protein-protein interactions and (Winter et al., (2012) Fragment-based Approaches to Targeting Protein-Protein Interactions: Structure-guided Drug Discovery. Q Rev Biophys. 45: 383