The Varani research group studies how proteins and nucleic acids interact with each other. The aim of the group is to understand at the physical chemical level how proteins bind nucleic acids and to exploit this knowledge to design new proteins, synthesize small molecule drugs that control human regulatory networks or repress viral replication. Members of the group use spectroscopic (NMR), crystallographic, computational and biochemical techniques.
The structure of RNA-binding protein Rntp1, co-determined by both NMR and crystallography.
Gene expression is central to biology - The human genome contains only 5 times as many genes as yeast. However, different genes are copied into messenger RNA differently and afterwards mRNAs are chemically processed, localized in the cell and translated into proteins differently. These processes multiply the number of distinct proteins coded by our genome, and makes highly evolved tissues, such as the brain, so astonishingly complex.
Proteins that bind nucleic acids play critical roles in disease progression. Since the majority of human genetic variation occurs outside protein coding regions, gene expression is also essential to understand why we respond differently to treatment or are susceptible to certain diseases. Misregulation of gene expression pathways or their exploitation by pathogens also lead to human disease. The Varani group is studying how viruses such as HIV and Hepatitis C exploit the human gene expression machinery to replicate. The group is also investigating the three-dimensional structure of telomerase, an enzyme composed of both RNA and protein components responsible for maintenance of the physical ends of chromosomes. Telomerase is a new target for anticancer therapy because it is selectively activated in >90% of all human cancers.
- Conformational change in RNA-binding protein CstF 64: The protein-RNA interface acquires significant mobility on the µs-ms time scale once GU-rich RNAs binds to it.
Control of gene expression depends on molecular recogniton events that remain to be understood at a fundamental physical chemical level.
The fundamental biological processes described above are carried out by specific RNA and DNA sequences and by the proteins that interact with them. It is therefore necessary to understand at the atomic level how protein and nucleic acids interact with each other. This task requires determining atomic structures of the proteins and RNA/DNA molecules that interact with each other and of their complexes, and to determine the thermodynamic and dynamic parameters associated with complex formation.
The fundamental goal of the research group is to degin proteins with new activities and synthesize new drugs to treat infectious and chronic disease. If we harness this knowledge, we would ultimately be able to rationally design new proteins and synthesize small molecule drugs that control gene expression networks. New designer poteins would provide ideal reagents to dissect gene expression pathways, while small molecule drugs that interfere with nucleic acid metabolism would be of tremendous value in the treatment of infectious disease.
- Structural determination of HIV-related BIV protein lead directly to design of novel β-hairpin peptidomimetic inhibitors.
New experimental and computational tools are being developed. By exploiting new NMR methods, and by interfacing closely with computational biology and theoretical chemistry (sequence analysis, homology modeling, structure-based drug design), the Varani group aims to determine structures of increasing complexity and to measure new experimental properties of biological interfaces. The goal is to develop predictive tools capable of describing the energetic and dynamic properties of such interfaces, so that the task of designing new interactions could be achieved successfully.
- Computational docking methodologies validated for modeling drug-RNA interactions.
A wide range of experimental and computational techniques are applied. Students and post-doctoral fellows in the group use NMR spectroscopy, X-ray crystallography, computational biology and biochemical techniques: often all of these tools are used by a single student to tackle a specific problem.
- Structure of telomerase protein-RNA complex (hTER/Box H /ATA assembly) and functional pathway.