“The joy of discovery is certainly the liveliest that the mind of man can ever feel”
- Claude Bernard -
The Georgieva research group studies the structure and function of membrane proteins from human pathogens and human membrane-interacting proteins linked to cancer.
We use multi-disciplinary approaches including biochemical, biophysical and structural biology methods and techniques to learn protein physiological mechanisms or malfunction at the molecular level.
Our major projects are:
1. Viral proteins in cellular membranes: mechanisms of function and inhibition
Our current emphasis is on viroporins. These are hydrophobic viral proteins, which reside in the cellular membranes. Viroporins self-oligomerize to form ion-specific channels or size-limited unspecific pores. Viroporins are encoded by most of the clinically relevant viruses, e.g. hepatitis C virus (HCV), human immuno deficiency virus (HIV), influenza A and B viruses (IAV and IBV), coronaviruses (CoV-s), poliovirus, human T-cell leukemia virus type-1 (HTLV-1). These proteins play critical role in virus assembly and budding, as well as in supporting virus adaptation and proliferation by triggering apoptosis and modifying signaling pathways required for virus survival in the host cell. Thus, viroporins are recognized as druggable targets to gain control over viral infections. However, their mechanisms of function and inhibition are poorly understood. Our effort is directed towards uncovering molecular details of viroporins and understanding their structure-function relationship. Further, we aim at learning how anti-viral drugs affect viroporins structure and structural dynamics leading to protein inhibition. The emphasis is on viroporins from oncogenic viruses.
2. Molecular mechanisms of bacterial membrane exporters
Bacterial integral membrane transporters are responsible for key physiological functions by mediating the uptake of nutrients and removal of unwanted products or toxic compounds out of the bacterial cell. Thus, these proteins enable the bacterial cell to maintain its essential cytoplasmic content, supporting cell survival, growth and proliferation. In harmful bacteria, these proteins are among the primary targets for drugs, ideally inhibiting their function and thereby suppressing the pathogen development.
Georgieva’s lab is interested in understanding the molecular mechanisms of membrane exporters in pathogenic bacteria with emphasis on the exporters of Mycobacterium tuberculosis (Mtb). Mtb constitutes a serious public health concern since the individuals infested with Mtb are under high risk of developing tuberculosis (TB). TB is one of the most devastating, hard-to-control infectious diseases, often leading to severe health complications and in many cases death. TB is among the leading causes of mortality worldwide but the means to prevent and treat this disease are very limited. Threfore, understanding the structure and function of essential Mtb proteins is instrumental for the development of efficient anti-Mtb pharmaceuticals. Our focus is on Mtb membrane exporters. We aim at characterizing and understanding the structure-function relationship underlying the molecular mechanisms of these proteins.
3. Molecular mechanisms of human multi-domain multi-functional proteins in signaling cascades: from physiological function to malfunction and cancer
We study the molecular mechanisms of human proteins involved in signal transduction at the membrane sites. Our focus is on multi-functional multi-domain proteins, which communicate with both cytosolic and membrane proteins. For the fulfilment of their physiological functions, both intra- and inter-domain structural communications are required. We aim at elucidating the conformational dynamics underlying these proteins function and understanding the structural basis for their interaction with other protein/lipid partners. Further, we aim at identifying how mutations affect the function of these proteins leading to cancer.