Dr. Kimber

Email: mkimber@uoguelph.ca

Office: SCIE 3456
Ext: 52568
Lab: SCIE 3403
Ext.: 58584

Profile

I was born in Great Britain, raised in South Africa, and have lived in Canada since my late teens. It was clear to me since childhood that I was going to study science, but I ended a structural biologist, as opposed to say, a geologist or astronomer, as much by happenstance as anything else. While doing a summer research project on catalytic RNAs as an undergraduate, I became intrigued by the notion that biological macromolecules can be looked at as strangely engineered three dimensional machines that could, with the right tools, be visualized, prodded, analyzed, taken apart and put back together. Following this interest lead to me entering graduate studies as a crystallographer in the lab of Dr. Emil Pai at the University of Toronto. After completing my graduate work I elected to forgo the traditional post-doctoral studies, and instead accepted a senior scientist position at a new biotech company in Toronto, Affinium Pharmaceuticals. Here I used structural biology as a key technology in helping develop new drug candidates, predominantly antimicrobials. I joined the University of Guelph in 2005.

Education

B.Sc. (Hons) – University of Toronto, 1993
Ph.D. University of Toronto, 2000

Research

Understanding the mechanistic details of how proteins recognize, manipulate and modify other molecules requires detailed knowledge of their structures. In my lab, x-ray crystallography is used as the primary tool to probe the molecular architecture of biological objects; the resulting detailed, three-dimensional models provide the context for interpreting established research findings and generating concrete functional hypothesis. These are then tested using further biochemical experiments to tease out the critical structure-function relationships.

At present, my lab is primarily focused on elucidating the structural organization of the carboxysome. Carboxysomes are large (up to 200 nm), icosahedral bodies found in the cytoplasm of cyanobacteria that catalyse the critical reaction that incorporates atmospheric CO2 into nascent sugars. Carboxysomes are made exclusively of protein, with a thin shell which is built from a handful of small proteins by tiling thousands of copies into continusous triangular sheets. The interior core is stuffed primarily with the CO2 fixing enzyme, RuBisCO, but also contains several other proteins that mediate a complex network of interactions necessary to structure and organize the body. The carboxysome appears to promote efficient carbon fixation by using its shell to confine CO2 near RuBisCO so that it is fixed, rather than escaping by diffusing through the cellular membranes. Most models of their functioning therefore imply that the shell traps CO2 but allows bicarbonate and other metabolites to pass – i.e. it effectively functions as a selectively permeable, but purely protein, membrane. Above and beyond this effect, the supermolecular organization of this complex possibly results in the emergence of new functional properties that further promote the efficiency of this critical biochemical process. My laboratory is using crystallography to solve the structures of individual carboxysome components, while in parallel using a variety of techniques to investigate their higher order organization. Ultimately we aim to understand the structural basis of the carboxysome’s unique properties.

In addition to this primary research theme, the lab generally has at least a few side projects underway (often with external collaborators) not wholly related to the main research theme; examples include our recently published work on cyanophycinase, and the proteins involved in LPS export.

Selected Publications

Peña KL, Castel SE, de Araujo C, Espie GS, Kimber MS. (2010)
Structural basis of the oxidative activation of the carboxysomal γ-carbonic anhydrase, CcmM. Proc Natl Acad Sci U S A. 107(6):2455-60.

Law AM, Lai SW, Tavares J, Kimber MS. (2009)
The structural basis of β-peptide-specific cleavage by the serine protease cyanophycinase.
J Mol Biol.;392(2):393-404.

Sun W, Shahinas D, Bonvin J, Hou W, Kimber MS, Turnbull J, Christendat D. (2009)
The crystal structure of Aquifex aeolicus prephenate dehydrogenase reveals the mode of tyrosine inhibition.
J Biol Chem. 284(19):13223-32.

Larue K, Kimber MS, Ford R, Whitfield C. (2009)
Biochemical and structural analysis of bacterial O-antigen chain length regulator proteins reveals a conserved quaternary structure.
J Biol Chem. 284(11):7395-403.
 
Jorgensen R, Purdy AE, Fieldhouse RJ, Kimber MS, Bartlett DH, Merrill AR. (2008)
Cholix toxin, a novel ADP-ribosylating factor from Vibrio cholerae.
J Biol Chem. 283(16):10671-8.

Cuthbertson L, Kimber MS, Whitfield C. (2007)
Substrate binding by a bacterial ABC transporter involved in polysaccharide export
Proc Natl Acad Sci U S A. 104(49):19529-34.

Gribun A, Kimber MS, Ching R, Sprangers R, Fiebig KM, Houry WA. (2005)
The ClpP double ring tetradecameric protease exhibits plastic ring-ring interactions, and the N termini of its subunits form flexible loops that are essential for ClpXP and ClpAP complex formation.
J Biol Chem. 280(16):16185-96.

Kimber MS, Martin F, Lu Y, Houston S, Vedadi M, Dharamsi A, Fiebig KM, Schmid M, Rock CO. (2004)
The structure of (3R)-hydroxyacyl-acyl carrier protein dehydratase (FabZ) from Pseudomonas aeruginosa.
J Biol Chem. 279(50):52593-602.

Kimber MS, Vallee F, Houston S, Necakov A, Skarina T, Evdokimova E, Beasley S, Christendat D, Savchenko A, Arrowsmith CH, Vedadi M, Gerstein M, Edwards AM. (2003)
Data mining crystallization databases: knowledge-based approaches to optimize protein crystal screens.
Proteins. 51(4):562-8.

Kimber MS, Nachman J, Cunningham AM, Gish GD, Pawson T, Pai EF. (2000)
Structural basis for specificity switching of the Src SH2 domain.
Mol Cell. Jun;5(6):1043-9.

Kimber MS, Pai EF. (2000)
The active site architecture of Pisum sativum β-carbonic anhydrase is a mirror image of that of α-carbonic anhydrases.
EMBO J. 19(7):1407-18.

Recruiting

I am presently looking to take on a new graduate student, with a start date of September 2010. Feel free to contact me by email if you are interested.

Teaching

MCB*4050 - Protein and Nucleic acid Structure
MCB*6370 - Protein Structure and Bioinformatics

Graduate Students

Bozena Samborska (M.Sc.)

Former lab members

Kerry Peña (M.Sc.)

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