Experimental Medical Science

Faculty of Medicine | Lund University


Medical Structural Biology

karin lindkvist

Karin Lindkvist
PhD, Associate Professor
+46 0734-222786

It is well known that proteins are very specific, readily discriminating between substrates with quite similar structures. This unique specificity of proteins is essential for life in health and disease. Molecular recognition is a fundamental aspect of life processes ranging from, e.g. protein-ligand interactions in regulatory and signaling networks to the formation of macromolecular assemblies.The immune system in our body is capable of specifically recognizing and selectively eliminating foreign microorganism and molecules (i.e., foreign antigen). This specificity is essential for us to be able to discriminate between what is our own body and what is foreign. However, it is not only in the immune system the specificity of proteins is essential for life. Virtually every property that characterizes a living organism is affected by proteins and its specificity. Proteins store and transport particles, they transmit information between and in cells, some proteins control the passage of molecules across the membranes, they control gene expression, they are the crucial components of muscles and some provide the filamentous architecture within cells. In this project we plan to reveal the structural and functional relationship of disease related molecules, soluble, as well as, trans-membrane proteins.

Interactions between macromolecules in general, and between proteins in particular, are essential for any life process. Examples include transfer of information, inhibition or activation of function, molecular recognition as in the immune system, assembly of macromolecular structures, molecular transport and more. Structural biology and in particular X-ray crystallography reveals an atomic picture on how proteins and protein complexes assemblies. We have an interest in thestructural biology of medicine and hence we have created a medical structural biology research unit at Lund University.

Structural biology of membrane proteins

Crystal structure of water transporter
Crystal structure of water transporter, determined to 1.1Å resolution, PLoS Biology 2009

Membrane proteins are of critical importance to nearly every aspect of cell physiology, comprising one-quarter to one-third of all proteins. Despite major efforts in studying membrane proteins two main problems have hampered the elucidation of detailed structural information. First, it is difficult to produce and isolate membrane proteins in an active form in quantities required for structural analyses. Secondly, it is notoriously difficult to obtain crystals of membrane proteins. Target proteins for us are central regulators of mammalian carbon and energy metabolism, and central regulators in cancer; glucose and glycerol transporters. Detailed knowledge of the structure of these target proteins would open for the possibility to exploit such proteins and their regulation in treatment of many diseases, such as diabetes, obesity and cancer.

Structural biology of the immunesystem

crystal structure of the ternary complex between mhc superantigen and tcr
Crystal structure of the ternary complex between MHC, superantigen and TCR, Nature Commun. 2010

Here we work on proteins that are the essential players of the acquired immune system, thus proteins that can discriminate between foreign and self-antigens. The main defenders in the acquired immunesystem are the T cells. Hence, understanding the specificity of the T cell receptor is extremely important. In addition, superantigens (toxins secreted by S. aureus) causes food poisoning, Scarlet Fever, Toxic Shock syndrome, Kawasaki Syndrome, Necrotizing Fasciitis and they have been implicated in autoimmune diseases, Rheumatic Fever and AIDS. Thus, there is an instant urge to comprehend the biology of these molecules to be able to understand and in the future treat diseases caused by them. Taken together, our goal is to retrieve a detailed knowledge of the structure and specificity of superantigens and T cell receptors, which would be an important contribution to understanding human physiology in health and disease.

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