James M. Hogle

Department of Biological Chemistry and Molecular Pharmacology
Harvard Medical School
Building C, Room 122
240 Longwood Avenue
Boston, MA 02115
Tel: (617) 432-3918
Fax: (617) 432-4360
Email: jhogle@hms.harvard.edu
4 postdoctoral fellows, 1 graduate student

Research in the Hogle lab employs a variety of biophysical, biochemical and molecular approaches to probe the relationship between virus structure and function. The work in the lab is currently focused in four main areas 1) the cell entry pathway of poliovirus and related picornaviruses, 2) viral RNA-protein interactions, 3) herpes virus relication proteins, 4) antiviral design.

1) Although poliovirus and related small icosahedral viruses are relatively simple and arguably the best understood viral pathogens, they must perform a variety of biological functions at various stages of their life cycle, many of which, including cell-entry, remain poorly understood. Understanding the cell entry pathway of simple viruses poses structural questions that span more than six orders of magnitude in scale ranging from the atomic level (tenths of nanometers) to the cellular level (tens of microns). Our studies of poliovirus cell entry therefore employ a multidisciplinary approach, including the use of single molecule techniques to follow the pathways leading to release of the viral genome during normal infection (in collaboration with Xiaowei Zhuang), the development of receptor- decorated liposomes and tethered bilayers as simple model systems for biochemical and structural characterization of the early events during infection, structural studies of soluble and membrane-bound virus-receptor complexes and cell entry intermediates using x-ray crystallography and electron microscopy, and electron tomography, and structural studies of cell entry intermediates in cells using electron tomography. 2) In collaboration with Lee Gehrke, we have recently solved the structure of a complex between a structural motif in the 3’ UTR of alfalfa mosaic virus and a peptide from the N-terminus of the capsid protein that is required for the initiation of infection. We are working to extend these studies to include RNA protein complexes that are implicated in priming RNA replication and in the regulation of translation and replication in poliovirus. 3) In collaboration with Don Coen, we have initiated a program of structural studies of essential proteins from herpes viruses, with a ultimate goal of providing a molecular model of the entire replisome. We have recently solved the structure of the processivity factor from herpes simplex virus (UL42) in complex with a peptide from the C-terminus of the catalytic subunit of the polymerase and the processivity factor from cytomegalovirus (UL44) alone and in complex with a peptide from the C-terminus of its polymerase. 4) Our interest in structures of viruses and viral proteins has naturally led us to investigate methods for using the structures to design antiviral drugs. We are currently developing methods in which the structures are used to develop templates for structurally-biased combinatorial libraries, and the libraries are screened for ligands with antiviral activity.

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