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Research

Biological systems - including the simplest cells - exhibit a broad range of functions to thrive in their environment. Research in the Imperial College Centre for Synthetic Biology is focused on the possibility of engineering the underlying biochemical processes to solve many of the challenges facing society, from healthcare to sustainable energy. In particular, we model, analyse, design and build biological and biochemical systems in living cells and/or in cell extracts, both exploring and enhancing the engineering potential of biology.

As part of our research we develop novel methods to accelerate the celebrated Design-Build-Test-Learn synthetic biology cycle. As such research in the Centre for Synthetic Biology highly multi- and interdisciplinary covering computational modelling and machine learning approaches; automated platform development and genetic circuit engineering ; multi-cellular and multi-organismal interactions, including gene drive and genome engineering; metabolic engineering; in vitro/cell-free synthetic biology; engineered phages and directed evolution; and biomimetics, biomaterials and biological engineering.

Publications

Citation

BibTex format

@article{Hazel:2017:10.1002/cmdc.201600535,
author = {Hazel, P and Kroll, SH and Bondke, A and Barbazanges, M and Patel, H and Fuchter, MJ and Coombes, RC and Ali, S and Barrett, AG and Freemont, PS},
doi = {10.1002/cmdc.201600535},
journal = {Chemmedchem},
pages = {372--380},
title = {Inhibitor selectivity for cyclin-dependent kinase7: a structural, thermodynamic, and modelling study},
url = {http://dx.doi.org/10.1002/cmdc.201600535},
volume = {12},
year = {2017}
}

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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Deregulation of the cell cycle by mechanisms that lead to elevated activities of cyclin-dependent kinases (CDK) is a feature of many human diseases, cancer in particular. We identified small-molecule inhibitors that selectively inhibit CDK7, the kinase that phosphorylates cell-cycle CDKs to promote their activities. To investigate the selectivity of these inhibitors we used a combination of structural, biophysical, and modelling approaches. We determined the crystal structures of the CDK7-selective compounds ICEC0942 and ICEC0943 bound to CDK2, and used these to build models of inhibitor binding to CDK7. Molecular dynamics (MD) simulations of inhibitors bound to CDK2 and CDK7 generated possible models of inhibitor binding. To experimentally validate these models, we gathered isothermal titration calorimetry (ITC) binding data for recombinant wild-type and binding site mutants of CDK7 and CDK2. We identified specific residues of CDK7, notably Asp155, that are involved in determining inhibitor selectivity. Our MD simulations also show that the flexibility of the G-rich and activation loops of CDK7 is likely an important determinant of inhibitor specificity similar to CDK2.
AU  - Hazel,P
AU  - Kroll,SH
AU  - Bondke,A
AU  - Barbazanges,M
AU  - Patel,H
AU  - Fuchter,MJ
AU  - Coombes,RC
AU  - Ali,S
AU  - Barrett,AG
AU  - Freemont,PS
DO  - 10.1002/cmdc.201600535
EP  - 380
PY  - 2017///
SN  - 1860-7187
SP  - 372
TI  - Inhibitor selectivity for cyclin-dependent kinase7: a structural, thermodynamic, and modelling study
T2  - Chemmedchem
UR  - http://dx.doi.org/10.1002/cmdc.201600535
UR  - http://www.ncbi.nlm.nih.gov/pubmed/28125165
UR  - http://hdl.handle.net/10044/1/44859
VL  - 12
ER  -