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个人简介

My research in Peter Davies' lab involves the use of X-ray crystallography and molecular modelling to study both the calpain family of enzymes and ice-binding proteins. Calpains are a family of cysteine proteases that depend on the presence of Ca2+ to allow them to adopt an active conformation. We are studying their structures to try to understand the details of this activation process. We are also using X-ray crystallography and modelling to determine structures of the enyzme in combination with substrates and inhibitors for use in structure-based inhibitor design. Specific inhibitors may be useful in further research studies and as potential lead compounds for the development of pharmaceuticals. Ice-binding proteins (IBPs) can be divided into two main groups: antifreeze proteins (AFPs) that inhibit ice crystal growth and ice nucleating proteins (INPs) that stimulate ice crystal growth. AFPs bind to the surfaces of ice crystals and inhibit their growth at subzero temperatures, thereby protecting the host organism from freezing damage. We have hypothesized that AFPs bind to ice by first ordering water molecules at the protein's surface to be in an ice-like array. In order to explore this idea, we are using X-ray crystallography combined with homology modelling, molecular dynamics and site-directed mutagenesis to examine the ordering of water molecules around the proteins' surfaces. INPs appear to differ from AFPs predominantly by the size of their ice-binding site. We are attempting to engineer INPs from AFPs and vice versa.

研究领域

My research in collaboration with Peter Davies' lab involves the use of X-ray crystallography and molecular modelling to study both the calpain family of enzymes and ice-binding proteins. Calpains are a family of cysteine proteases that depend on the presence of Ca2+ to allow them to adopt an active conformation. We are studying their structures to try to understand the details of this activation process. We use X-ray crystallography and modelling to determine structures of the enyzme in combination with substrates and inhibitors for use in structure-based inhibitor design. Specific inhibitors may be useful in further research studies and as potential lead compounds for the development of pharmaceuticals for the treatment after ischemic reperfusion events. Antifreeze proteins (AFPs) are one class of ice-binding proteins that bind to the surfaces of ice crystals and inhibit their growth at subzero temperatures, thereby protecting the organism from freezing damage. We have hypothesized that AFPs bind to ice by first ordering water molecules at the protein's surface to be in an ice-like array. In order to explore this idea, we are using X-ray crystallography and homology modelling along with site-directed mutagenesis to examine the ordering of water molecules around the proteins' surfaces. Another class of ice-binding proteins are those that nucleate the formation of ice (ice-nucleating proteins, INPs) that appear to differ from AFPs predominantly by the size of their ice-binding site. We are attempting to explore this relationship by engineering INPs from AFPs and vice versa.

近期论文

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Sun T, Gauthier SY, Campbell RL, Davies PL (2015) Revealing Surface Waters on an Antifreeze Protein by Fusion Protein Crystallography Combined with Molecular Dynamic Simulations. J Phys Chem B. 119.12808-15. PubMed 26371748. (doi: 10.1021/acs.jpcb.5b06474) Basu, K, Graham, LA, Campbell, RL and Davies, PL (2015) Flies expand the repertoire of protein structures that bind ice. Proc Natl Acad Sci U S A. 112(3), 737-42. PubMed: 25561557 (doi: 10.1073/pnas.1422272112.) Low, KE, Partha, SK, Davies, PL, Campbell, RL (2014) Allosteric inhibitors of calpains: Reevaluating inhibition by PD150606 and LSEAL. Biochim Biophys Acta. 1840(12), 3367-3373.PubMed: 25196359 Vance, TDR, Olijve, LLC, Campbell, RL, Voets, IK, Davies, PL, Guo, S, (2014) Ca2+-stabilized adhesin helps an Antarctic bacterium reach out and bind ice. Bioscience Reports. 34(4). PubMed: 24892750 Partha, SK, Ravulapalli, R, Allingham, JS, Campbell, RL, Davies, PL (2014) Crystal structure of calpain-3 penta-EF-hand domain: A homodimerized PEF family member with calcium bound at the fifth EF-hand. FEBS Journal. 281(14), 3138-49. PubMed: 24846670 Sun,T, Lin, F-H, Campbell, RL, Allingham, JS, and Davies, PL (2014) An antifreeze protein folds with an interior network of over 400 semi-clathrate waters. Science 343(6172), 795-8. PubMed: 24531972 Guo, S, Garnham, CP, Partha, SK, Campbell, RL, Allingham, JS, Davies, PL (2013) Role of Ca2+ in folding the tandem β-sandwich extender domains of a bacterial ice-binding adhesion. FEBS Journal Ref. no.: FJ-13-0467.R1.PubMed: 24024640 Campbell RL, Davies PL (2012) Structure-function relationships in calpains. Biochem J. 447, 335-51 PubMed: 23035980 Middleton, AJ, Marshall, CB, Faucher, F, Bar-Dolev, M, Braslavsky, I, Campbell, RL, Walker, VK and Davies, PL (2012) Antifreeze protein from freeze-tolerant grass has a beta-roll fold with an irregularly structured ice-binding site. J. Mol. Biol. 416, 713-724 PubMed: 22306740 Garnham, CP, Campbell, RL, Walker, VK and Davies, PL (2011) Novel dimeric beta-helical model of an ice nucleation protein with bridged active sites. BMC Structural Biology. 11:36 PubMed: 21951648 Garnham, CP, Campbell, RL and Davies, PL (2011) Anchored clathrate waters bind antifreeze proteins to ice. Proc Natl Acad Sci 108, 7363-7367. PubMed: 21482800 PubMed Central: PMC3088597 Kelly, JC, Cuerrier, D, Graham, LA, Campbell, RL, and Davies, PL (2009) Profiling of calpain activity with a series of FRET-based substrates. Biochim Biophys Acta. 1794, 1505-1509. PubMed: 19555780 Garnham, CP, Hanna, RA, Chou, JS, Low, KE, Gourlay, K, Campbell, RL, Beckmann, JS and Davies, PL (2009) Limb-girdle muscular dystrophy type 2A can result from accelerated autoproteolytic inactivation of calpain 3. Biochemistry 48, 3457-3467. PubMed: 19226146 Ravulapalli, R, Campbell, RL, Gauthier, SY, Dhe-Paganon, S and Davies PL (2009) Distinguishing between calpain heterodimerization and homodimerization. FEBS J. 276, 973-982. PubMed: 19215300 Hanna, RA, Campbell, RL and Davies, PL (2008) Calcium-bound structure of calpain and its mechanism of inhibition by calpastatin. Nature 456, 409-412. PubMed: 19020623 Qian, J, Cuerrier, D, Davies, PL, Li, Z, Powers, JC and Campbell, RL (2008) Cocrystal structures of primed side-extending alpha-ketoamide inhibitors reveal novel calpain-inhibitor aromatic interactions. J. Med. Chem. 51, 5264-5270. PubMed: 18702462 Graham, LA, Marshall, CB, Lin, F-H, Campbell, RL and Davies, PL (2008) Hyperactive antifreeze protein from fish contains multiple ice-binding sites. Biochemistry 47, 2051-2063. PubMed: 18225917 Garnham, CP, Gilbert, JA, Hartman, CP, Campbell, RL, Laybourn-Parry, J and Davies PL (2008) A Ca2+-dependent bacterial antifreeze protein domain has a novel beta-helical ice-binding fold. Biochem J. 411, 171-180. PubMed: 8095937 Cuerrier, D, Moldoveanu, T, Campbell, RL, Kelly, J, Yoruk, B, Verhelst, SHL, Greenbaum, D, Bogyo, M and Davies, PL (2007) Development of calpain-specific inactivators by screening of positional-scanning epoxide libraries. J. Biol. Chem. 282, 9600-9611. PubMed: 17218315 Cuerrier, D, Moldoveanu, T, Inoue, J, Davies, PL, Campbell RL (2006) Calpain Inhibition by Ketoamide and Cyclic Hemiacetal Inhibitors Revealed by X-ray Crystallography Biochemistry, 45, 7446-7452. PubMed: 16768440

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