Marianne A. Grant, PhD
Instructor in Medicine
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, Dana 270E
Boston, MA 02215
Marianne Grant is a structural biologist at the Beth Israel Deaconess Medical Center and an Instructor in Medicine at Harvard Medical School. She received her PhD from Brown University within the Pharmacology, Biotechnology and Physiology Department studying neuromuscular and neuronal ion channel structure-function using nuclear magnetic resonance NMR spectroscopy. She went on in postdoctoral research to study the structure and function of pro- and anticoagulant proteins in the Division of Hemostasis and Thrombosis at the BIDMC with Dr. Alan Rigby. In 2005 Dr. Grant joined the Division of Molecular and Vascular Medicine and became a member of the CVBR.
Protein Structure-Function and Biomolecular Recognition
My laboratory investigates the three dimensional structure, function, and interactions of proteins at the atomic level. Our aim is to apply the tools of structural biology to an understanding of molecular structure-function, particularly for macromolecules that are potential targets for therapeutic intervention in human disease. Our work makes use of a combination of molecular, biochemical, and biophysical techniques. In particular, we use heteronuclear nuclear magnetic resonance (NMR) spectroscopy to determine the three-dimensional structures of proteins. We also use computational analyses and bioinformatics to investigate protein structure-function relationships. This aspect of our work concerns the in silico prediction of protein structure, the molecular docking and dynamic simulation of molecular interactions between proteins or between proteins and DNA, and the development of computational tools to further elucidate structure-function mechanisms from databases of protein structure information. Topics we are currently investigating include i.) gene regulation in the vascular endothelium, and ii.) molecular pathways of growth inhibition and apoptosis.
Gene Regulation in the Vascular Endothelium
We are investigating molecular mechanisms of gene regulation important in human vascular systems, with an emphasis on gene expression that promotes or inhibits vascular endothelial cell growth control and angiogenesis. Toward this end, the fundamental aspects of protein structure, molecular recognition, and conformational alteration in protein transcription factor families are currently under investigation. In addition, we are interested in studying the interactions between transcription factors that synergistically control gene expression and are implicated in human vascular dysfunctions, including cardiovascular disease and diabetes, as well as inherited renal disease.
Molecular Pathways of Growth Inhibition and Apoptosis
We are investigating the structure-function of proteins playing critical roles in growth inhibition and apoptosis. In particular, these proteins function as adhesives or adaptors in multimeric protein complexes crucial to signal transduction pathways and protein translocation mechanisms that are important in cell growth control. Our aim is to advance our molecular understanding of these interactions and reveal the mechanisms by which certain mutations affect these associations.
New and Noteworthy Publications
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Grant, MA. (2008) LMX1b mutations of Nail-Patella Syndrome disrupt homeodomain DNA-binding, domain structure, and stability, submitted.
This study describes the structural assessment of disease-linked mutations in a homeodomain/DNA complex, providing significant insight into the effects of point mutations within homeodomain architecture and function.
Grant, MA, Baron, RM, Macias, AV, Perrella, MA, Rigby, AC. (2008) Netropsin interference with HMGA1 AT-rich DNA binding attenuates NOS2 induction and improves outcomes from murine endotoxemic shock, submitted.
This study elucidates through biophysical and structural data the beneficial effect of netropsin on survival outcomes in a septic shock model through interference with HMGA transcription factor binding in the NOS2 promoter.
Grant, MA. (2008) Protein structure prediction in structure-based ligand design and virtual screening. Combinatorial Chemistry and High Throughput Screening, in press.
This article describes method advancements in protein structure prediction and assesses the application of predicted protein structures to structure-based ligand design.
Grant, MA, Lazo, ND, Lomakin A, Condron, MM, Arai, H, Yamin, G, Rigby, AC, Teplow, DB. (2007) Familial Alzheimer's Disease Mutations Alter the Stability of the Amyloid-b Protein Monomer Folding Nucleus, Proc. Natl. Acad. Sci USA, 104(42):16522-7.
This study reveals that gene mutations in the Amyloid-beta protein increase the flexibility of a small loop region of the protein that normally forms a stable turn. This elucidation will aid the design of novel therapeutics that prevent Amyloid-beta aggregation in familial Alzheimer's disease.
Grant, MA, Shanmugasundaram K., and Rigby AC. (2007) Conotoxin therapeutics: a pipeline for success? Expert. Opin. Drug Discov., 2(4): 453-68.
This article describes our work and others to understand the molecular interactions between antagonizing marine snail toxins and ion channel receptors to provide new pharmacological therapeutics to treat neurologic disorders.