Mark Searle

Contact

• workRoom A9 Centre for Biomolecular Sciences
  University Park
  Nottingham
  NG7 2RD
  UK
• work0115 951 3567
• mark.searle@nottingham.ac.uk
• http://darwin.chem.nottingham.ac.uk/group/index.html

Biography

Searle obtained his B.A. and M.A. in Chemistry from the University of Oxford in 1983 and 1985 respectively. His Ph.D. from the MRC, National Institute for Medical Research, Mill Hill, London followed in 1986. Three years as an Australian Research Council (ARC) Research Fellow preceded his return to the UK as a SERC/GLAXO Research Fellow in Cambridge from 1990 until 1995. In 1995, Dr. Searle was appointed as a Lecturer in Biological Chemistry at the University of Nottingham

Research Summary

Searle's research focuses on biomolecular structure, dynamics and interactions with the over arching theme of understanding non-covalent interactions in biomolecular recognition. Research areas… read more

Selected Publications

• SIMPSON, E. R., MELDRUM, J. K., BOFILL, R., CRESPO, M. D., HOLMES, E. and SEARLE, M. S., 2005. Engineering Enhanced Protein Stability through beta-Turn Optimization: Insights for the Design of Stable Peptide beta-Hairpin Systems Angewandte Chemie International Edition. Volume 44(Number 31), 4939-4944
• BOFILL, R. and SEARLE, M. S., 2005. Engineering Stabilising b-Sheet Interactions into a Conformationally Flexible Region of the Folding Transition State of Ubiquitin Journal of Molecular Biology. VOL 353(NUMBER 2), 373-384
• BOFILL, R., SIMPSON, E.R., PLATT, G.W., CRESPO, M.D. and SEARLE, M.S., 2005. Extending the folding nucleus of ubiquitin with an independently folding β-hairpin finger: hurdles to rapid folding arising from the stabilisation of local interactions Journal of Molecular Biology. 349(1), 205-221
• SEARLE, M.S., 2005. Design and stability of peptide beta-sheets. In: Protein folding handbook Wiley-VCH Verlag GmbH & Co, Weinheim, Germany. 314-342

• View all publications

Current Research

Searle's research focuses on biomolecular structure, dynamics and interactions with the over arching theme of understanding non-covalent interactions in biomolecular recognition. Research areas include the structure and folding of DNA, in particular hairpin loops and quadruplex structures, and studies of DNA-ligand interactions using a wide range of structural/biophysical tools. The Searle group has pioneered work on the design and folding of peptide beta-sheets for use in quantitative studies of weak interactions, and structure, dynamics and co-operativity in peptide folding. More recently, the folding pathways of proteins have been investigated using protein engineering methods coupled with structural and biophysical analysis to map and manipulate kinetic pathways. The group also has an NMR structural biology programme with a particular interest in protein-protein interactions related to dysfunction polyubiquitin chain recognition. The research activities are broadly based in NMR structural biology and biophysics, with the group accommodated in excellent facilities within the new Centre for Biomolecular Sciences.

• CHEN, P., EVANS, C.-L., HIRST, J.D. and SEARLE, M.S., 2011. Structural insights into the two sequential folding transition states of the PB1 domain of NBR1 from phi-value analysis and biased molecular dynamics simulations Biochemistry. 50, 125-135
• GARNER TP, STRACHAN J, SHEDDEN EC, LONG JE, CAVEY JR, SHAW B, LAYFIELD R and SEARLE MS, 2011. Independent interactions of ubiquitin-binding domains in a ubiquitin-mediated ternary complex. Biochemistry. 50(42), 9076-87
• EDWARDS, J, MALAURIE, E, KONDRASHOV, A, LONG, J, DE MOOR, CH, SEARLE, MS and EMSLEY, J, 2011. Sequence Determinants For The Tandem Recognition Of Ugu And Cug Rich Rna Elements By The Two N-Terminal Rrms Of Celf1 Nucleic Acids Research. 39(19), 8638-8650
• LONG J, GARNER TP, PANDYA MJ, CRAVEN CJ, CHEN P, SHAW B, WILLIAMSON MP, LAYFIELD R, SEARLE MS, 2010. Dimerisation of the UBA domain of p62 inhibits ubiquitin binding and regulates NF-kappaB signalling. Journal Molecular Biology. 396(1), 178-94
• BALKWILL, GD, DERECKA, K, GARNER, TP, HODGMAN, C, FLINT, APF and SEARLE, MS, 2009. Repression Of Translation Of Human Estrogen Receptor Alpha By G-Quadruplex Formation Biochemistry. 48(48), 11487-11495
• LONG, J, GALLAGHER, T, CAVEY, JR, SHEPPARD, PW, RALSTON, S, LAYFIELD, R, SEARLE, MS, 2008. Ubiquitin Recognition by the Ubiquitin-associated Domain of p62 Involves a Novel Conformational Switch. Journal of Biological Chemistry. 283(9), 5427-5440
• LAYFIELD, R, SEARLE, MS, 2008. Disruption of ubiquitin-mediated processes in diseases of the brain and bone. Biochemical Society Transactions. 36(Pt 3), 469-71
• EVANS, C. L., LONG, J. E., GALLAGHER, T. R., HIRST, J. D. and SEARLE, M. S., 2008. Conformation and dynamics of the three-helix bundle UBA domain of p62 from experiment and simulation PROTEINS -NEW YORK-. VOL 71(NUMBER 1), 227-240
• DELAHAY, R.M, BALKWILL, G.D, BUNTING, K.A, EDWARDS, W, ATHERTON, J.C and AND SEARLE, M.S., 2008. The highly repetitive region of the Helicobacter pylori CagY protein comprises tandem arrays of an alpha-helical repeat module. Journal Molecular Biology. 377(3), 956-71
• REA, ANITA M, SIMPSON, EMMA R, CRESPO, MARIA D and SEARLE, MARK S, 2008. Helix mutations stabilize a late productive intermediate on the folding pathway of ubiquitin. Biochemistry. 47(31), 8225-36
• KOUVATSOS, N., THURSTON, V., BALL, K., OLDHAM, N.J., THOMAS, N.R. and SEARLE, M.S., 2007. Bile acid interactions with rabbit ileal lipid binding protein and an engineered helixless variant reveal novel ligand binding properties of a versatile beta-clam shell protein scaffold Journal of Molecular Biology. 371(5), 1365-1377
• BALKWILL, GRAHAM D, WILLIAMS, HUW E L and SEARLE, MARK S, 2007. Structure and folding dynamics of a DNA hairpin with a stabilising d(GNA) trinucleotide loop: influence of base pair mis-matches and point mutations on conformational equilibria. Organic and Biomolecular Chemistry. 5(5), 832-9
• CAVEY, J. R., RALSTON, S. H., SHEPPARD, P. W., CIANI, B., GALLAGHER, T. R. A., LONG, J. E., SEARLE, M. S. and LAYFIELD, R., 2006. Loss of ubiquitin binding is a unifying mechanism by which mutations of SQSTM1 cause Paget's disease of bone Calcified Tissue International. 78(5), 271-277
• KOUVATSOS, N., MELDRUM, J.K., SEARLE, M.S. and THOMAS, N.R., 2006. Coupling ligand recognition to protein folding in an engineered variant of rabbit ileal lipid binding protein. Chemical Communications. 44, 4623-4625
• SIMPSON, E. R., MELDRUM, J. K. and SEARLE, M. S., 2006. Engineering Diverse Changes in beta-Turn Propensities in the N-Terminal beta-Hairpin of Ubiquitin Reveals Significant Effects on Stability and Kinetics but a Robust Folding Transition State Biochemistry. VOL 45(NUMB 13), 4220-4230
• SEARLE, M.S. and BALKWILL, G.D., 2006. DNA quadruplex-ligand recognition: structure and dynamics. In: Quadruplex Nucleic Acids Royal Society of Chemistry, Cambridge, UK. 132-154
• CRESPO, M.D., SIMPSON, E.R. and SEARLE, M.S., 2006. Population of on-pathway intermediates in the folding of ubiqitin Journal of Molecular Biology. 360(5), 1053-1066
• CAVEY, J. R., RALSTON, S. H., HOCKING, L. J., SHEPPARD, P. W., CIANI, B., SEARLE, M. S. and LAYFIELD, R., 2005. Loss of ubiquitin-binding associated with Paget's disease of bone p62 (SQSTM1) mutations Journal of Bone and Mineral Research. 20(4), 619-624
• BOFILL, R., SIMPSON, E.R., PLATT, G.W., CRESPO, M.D. and SEARLE, M.S., 2005. Extending the folding nucleus of ubiquitin with an independently folding β-hairpin finger: hurdles to rapid folding arising from the stabilisation of local interactions Journal of Molecular Biology. 349(1), 205-221
• BOFILL, R. and SEARLE, M. S., 2005. Engineering Stabilising b-Sheet Interactions into a Conformationally Flexible Region of the Folding Transition State of Ubiquitin Journal of Molecular Biology. VOL 353(NUMBER 2), 373-384
• SIMPSON, E. R., MELDRUM, J. K., BOFILL, R., CRESPO, M. D., HOLMES, E. and SEARLE, M. S., 2005. Engineering Enhanced Protein Stability through beta-Turn Optimization: Insights for the Design of Stable Peptide beta-Hairpin Systems Angewandte Chemie International Edition. Volume 44(Number 31), 4939-4944
• SEARLE, M.S., 2005. Design and stability of peptide beta-sheets. In: Protein folding handbook Wiley-VCH Verlag GmbH & Co, Weinheim, Germany. 314-342
• HOCKING, LYNNE J, LUCAS, GAVIN J A, DAROSZEWSKA, ANNA, CUNDY, TIM, NICHOLSON, GEOFF C, DONATH, JUDIT, WALSH, JOHN P, FINLAYSON, CATRIONA, CAVEY, JAMES R, CIANI, BARBARA, SHEPPARD, PAUL W, SEARLE, MARK S, LAYFIELD, ROBERT and RALSTON, STUART H, 2004. Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: genotype phenotype correlation, functional analysis, and structural consequences. Journal of Bone and Mineral Research. 19(7), 1122-7
• LAYFIELD, R., CIANI, B., RALSTON, S. H., HOCKING, L. J., SHEPPARD, P. W., SEARLE, M. S. and CAVEY, J. R., 2004. Structural and functional studies of mutations affecting the UBA domain of SQSTM1 (p62) which cause Paget's disease of bone Biochemical Society Transactions. VOL 32(PART 5), 728-730
• SEARLE, M. S. and CIANI, B., 2004. Design of b-sheet systems for understanding the thermodynamics and kinetics of protein folding Current Opinion in Structural Biology. VOL 14(NUMBER 4), 458-464
• SEARLE, M.S., PLATT, G.W., BOFILL, R., SIMPSON, S.A. and CIANI, B., 2004. Incremental contribution to protein stability from a β hairpin "finger": limits on the stability of designed β hairpin peptides Angewandte Chemie International Edition. 43(15), 1991-1994
• SEARLE, M. S., 2004. Insights into Stabilizing Weak Interactions in Designed Peptide beta-Hairpins Biopolymers. VOL 76(PART 2), 185-195
• CRESPO, M. D., PLATT, G. W., BOFILL, R. and SEARLE, M. S., 2004. Context-dependent effects of proline residues on the stability and folding pathway of ubiquitin European Journal of Biochemistry. VOL 271(NUMBER 22), 4474-4484
• SEARLE, M. S., WILLIAMS, H. E. L., GALLAGHER, C. T., GRANT, R. J. and STEVENS, M. F. G., 2004. Structure and K^+ ion-dependent stability of a parallel-stranded DNA quadruplex containing a core A-tetrad Organic and Biomolecular Chemistry. VOL 2(NUMB 6), 810-812
• CIANI, B., LAYFIELD, R., CAVEY, J. R., SHEPPARD, P. W. and SEARLE, M. S., 2003. Structure of the ubiquitin-associated domain of p62 (SQSTM1) and implications for mutations that cause Paget's disease of bone Journal of Biological Chemistry. 278(39), 37409-37412
• PLATT, G. W., SIMPSON, S. A., LAYFIELD, R. and SEARLE, M. S., 2003. Stability and Folding Kinetics of a Ubiquitin Mutant with a Strong Propensity for Nonnative beta-Hairpin Conformation in the Unfolded State Biochemistry. VOL 42(PART 46), 13762-13771
• CIANI, B., JOURDAN, M. and SEARLE, M.S., 2003. Stabilisation of β-hairpin peptides by salt bridges: role of pre-organization in the energetic contribution of weak interactions Journal of the American Chemical Society. 125(30), 9038-9047
• SEARLE, M. S., MAYNARD, A. J. and WILLIAMS, H. E. L., 2003. DNA recognition by the anthracycline antibiotic respinomycin D: NMR structure of the intercalation complex with d(AGACGTCT)~2 Organic and Biomolecular Chemistry. VOL 1(NUMB 1), 60-66
• WILLIAMS, H.E., GAVATHIOTIS, E., GRANT, R.R., SEARLE, M.S. and STEVENS, M.F., 2003. RHPS4 selectivity for quadruplex DNA. Clinical Cancer Research. 9(16), 6083s-6083s
• GAVATHIOTIS, E. and SEARLE, M. S., 2003. Structure of the parallel-stranded DNA quadruplex d(TTAGGGT)~4containing the human telomeric repeat: evidence for A-tetrad formation from NMR and molecular dynamics simulations Organic and Biomolecular Chemistry. VOL 1(NUMB 10), 1650-1656
• GALLAGHER, C. T. and SEARLE, M. S., 2003. Drug-induced stabilisation of a mismatched C-T base pair in a DNA hairpin Chemical Communications. PART 15, 1814-1815
• GAVATHIOTIS, E., HEALD, R. A., STEVENS, M. F. and SEARLE, M. S., 2003. Drug Recognition and Stabilisation of the Parallel-stranded DNA Quadruplex d(TTAGGGT)4 Containing the Human Telomeric Repeat Journal of Molecular Biology. VOL 334(NUMBER 1), 25-36
• COLGRAVE, M. L., WILLIAMS, H. E. L. and SEARLE, M. S., 2002. Structure of a Drug-Induced DNA T-Bulge: Implications for DNA Frameshift Mutations Angewandte Chemie International Edition. VOL 41(PART 24), 4754-4756
• WILLIAMS, H. E. L., COLGRAVE, M. L. and SEARLE, M. S., 2002. Drug recognition of a DNA single strand break. Nogalamycin intercalation between coaxially stacked hairpins European Journal of Biochemistry. VOL 269(PART 6), 1726-1733
• COLGRAVE, M. L., BECK, J. L., SHEIL, M. M. and SEARLE, M. S., 2002. Electrospray ionisation mass spectrometric detection of weak non-covalent interactions in nogalamycin-DNA complexes Chemical Communications. PART 6, 556-557
• HARRIS, S A., GAVATHIOTIS, E., SEARLE, M S., OROZCO, M. and LAUGHTON, C A., 2001. Cooperativity in drug-DNA recognition: a molecular dynamics study Journal of the American Chemical Society. 123(50), 12658-12663
• GAVATHIOTIS, E., HEALD, R.A., STEVENS, M.F.G. and SEARLE, M.S., 2001. Recognition and stabilization of quadruplex DNA by a potent new telomerase inhibitor: NMR studies of the 2:1 complex of a pentacyclic methylacridinium cation with d(TTAGGGT)₄ Angewandte Chemie International Edition. 40(24), 4749-4751
• COLGRAVE, M. L., WILLIAMS, H. E. L. and SEARLE, M. S., 2001. Binding of anthracycline antibiotic nogalamycin to the site of a DNA single strand break engineered between two co-axially stacked hairpins Chemical Communications. PART 4, 315-316
• BOSTOCK-SMITH, C E, HARRIS, S A, LAUGHTON, C A and SEARLE, M A, 2001. Induced fit DNA recognition by a minor groove binding analogue of Hoechst 33258: fluctuations in DNA A tract structure investigated by NMR and molecular dynamics simulations. Nucleic Acids Research. 29(3), 693-702
• SHARMAN, G. J., GRIFFITHS-JONES, S. R., JOURDAN, M. and SEARLE, M. S., 2001. Effects of Amino Acid phi,psi Propensities and Secondary Structure Interactions in Modulating Halpha Chemical Shifts in Peptide and Protein beta-Sheet Journal of the American Chemical Society. VOL 123(PART 49), 12318-12324
• PLATT, G., CHUNG, C.-W. and SEARLE, M. S., 2001. Design of histidine-Zn^2^+ binding sites within a beta-hairpin peptide: enhancement of beta-sheet stability through metal complexation Chemical Communications. PART 13, 1162-1163
• JOURDAN, M. and SEARLE, M. S., 2001. Insights into the Stability of Native and Partially Folded States of Ubiquitin: Effects of Cosolvents and Denaturants on the Thermodynamics of Protein Folding Biochemistry. VOL 40(PART 34), 10317-10325
• SEARLE, M. S., 2001. Peptide models of protein beta-sheets: design, folding and insights into stabilising weak interactions PERKIN 2. PART 7, 1011-1020
• GRIFFITHS-JONES, S. R., MAYNARD, A. J., SHARMAN, G. J. and SEARLE, M. S., 1998. NMR evidence for the nucleation of a á-hairpin peptide conformation in water by an Asn-Gly type I' á-turn sequence Chemical Communications. NUMBER 7, 789-790
• MAYNARD, A. J. and SEARLE, M. S., 1997. NMR structural analysis of a á-hairpin peptide designed for DNA binding Chemical Communications. NUMBER 14, 1297-1298
• BOSTOCK-SMITH, C. E., EMBREY, K. J. and SEARLE, M. S., 1997. Enhanced binding of a hexacyclic amidine analogue of Hoechst 33258 to the minor groove of DNA: ^1H NMR and UV melting studies with the decamer duplex d(GGTAATTACC)~2 Chemical Communications. NUMBER 1, 121-122
• SHARMAN, G. J. and SEARLE, M. S., 1997. Dissecting the effects of cooperativity on the stabilisation of a de novo designed three stranded anti-parallel á-sheet Chemical Communications. NUMBER 20, 1955-1956
• SEARLE, M. S., WILLIAMS, D. H. and PACKMAN, L. C., 1995. A short linear peptide derived from the N-terminal sequence of ubiquitin folds into a water-stable non-native á-hairpin Nature Structural Biology. VOL 2(NUMBER 11), 999