Stephen Harrison - Academia.edu (original) (raw)
Papers by Stephen Harrison
Proceedings of the National Academy of Sciences, 2006
HIV-1 enters cells by membrane fusion, mediated by the trimeric viral envelope glycoprotein gp160... more HIV-1 enters cells by membrane fusion, mediated by the trimeric viral envelope glycoprotein gp160, which is processed by a single proteolytic cleavage into stably associated gp120 and gp41. The gp120/gp41 trimer can be triggered to undergo an irreversible conformational change. Using a protein-based assay designed to mimic the gp41 conformational change, we screened for small molecules that prevent the formation of postfusion gp41. Several compounds were identified. One set of structurally related molecules inhibited formation of a postfusion-like assembly with an IC 50 of ≈5 μM. The compounds also inhibited envelope-mediated membrane fusion in both cell–cell fusion and viral infectivity assays. Thus, our screen identifies effective fusion inhibitors. Tested against a panel of envelope proteins from primary HIV-1 isolates, the compounds inhibited fusion across a broad range of clades, including both M and T tropic strains. They bind in a highly conserved, hydrophobic pocket on the i...
Journal of molecular biology, Jan 16, 2017
Structure-based vaccine design depends on extensive structural analyses of antigen-antibody compl... more Structure-based vaccine design depends on extensive structural analyses of antigen-antibody complexes.Single-particle electron cryomicroscopy (cryoEM) can circumvent some of the problems of x-ray crystallography as a pipeline for obtaining the required structures. We have examined the potential of single-particle cryoEM for determining the structure of influenza-virus hemagglutinin (HA):single-chain variable-domain fragment complexes, by studying a complex we failed to crystallize in pursuing an extended project on the human immune response to influenza vaccines.The result shows that a combination of cryoEM and molecular modeling can yield details of the antigen-antibody interface, although small variation in the twist of the rod-likeHA trimer limited the overall resolution to about 4.5Å.Comparison of principal 3D classes suggests ways to modify the HA trimer to overcome this limitation. A closely related antibody from the same donor did yield crystals when bound with the same HA, g...
Science, 2005
The spike protein (S) of SARS coronavirus (SARS-CoV) attaches the virus to its cellular receptor,... more The spike protein (S) of SARS coronavirus (SARS-CoV) attaches the virus to its cellular receptor, angiotensin-converting enzyme 2 (ACE2). A defined receptor-binding domain (RBD) on S mediates this interaction. The crystal structure at 2.9 angstrom resolution of ...
Nature structural & molecular biology, 2008
Nature Structural & Molecular Biology is an integrated forum for structural and molecular studies... more Nature Structural & Molecular Biology is an integrated forum for structural and molecular studies. The journal places a strong emphasis on functional and mechanistic understanding of how molecular components in a biological process work together. Structural data may provide ...
Proceedings of the National Academy of Sciences, 2006
HIV-1 enters cells by membrane fusion, mediated by the trimeric viral envelope glycoprotein gp160... more HIV-1 enters cells by membrane fusion, mediated by the trimeric viral envelope glycoprotein gp160, which is processed by a single proteolytic cleavage into stably associated gp120 and gp41. The gp120/gp41 trimer can be triggered to undergo an irreversible conformational change. Using a protein-based assay designed to mimic the gp41 conformational change, we screened for small molecules that prevent the formation of postfusion gp41. Several compounds were identified. One set of structurally related molecules inhibited formation of a postfusion-like assembly with an IC 50 of ≈5 μM. The compounds also inhibited envelope-mediated membrane fusion in both cell–cell fusion and viral infectivity assays. Thus, our screen identifies effective fusion inhibitors. Tested against a panel of envelope proteins from primary HIV-1 isolates, the compounds inhibited fusion across a broad range of clades, including both M and T tropic strains. They bind in a highly conserved, hydrophobic pocket on the i...
Journal of molecular biology, Jan 16, 2017
Structure-based vaccine design depends on extensive structural analyses of antigen-antibody compl... more Structure-based vaccine design depends on extensive structural analyses of antigen-antibody complexes.Single-particle electron cryomicroscopy (cryoEM) can circumvent some of the problems of x-ray crystallography as a pipeline for obtaining the required structures. We have examined the potential of single-particle cryoEM for determining the structure of influenza-virus hemagglutinin (HA):single-chain variable-domain fragment complexes, by studying a complex we failed to crystallize in pursuing an extended project on the human immune response to influenza vaccines.The result shows that a combination of cryoEM and molecular modeling can yield details of the antigen-antibody interface, although small variation in the twist of the rod-likeHA trimer limited the overall resolution to about 4.5Å.Comparison of principal 3D classes suggests ways to modify the HA trimer to overcome this limitation. A closely related antibody from the same donor did yield crystals when bound with the same HA, g...
Science, 2005
The spike protein (S) of SARS coronavirus (SARS-CoV) attaches the virus to its cellular receptor,... more The spike protein (S) of SARS coronavirus (SARS-CoV) attaches the virus to its cellular receptor, angiotensin-converting enzyme 2 (ACE2). A defined receptor-binding domain (RBD) on S mediates this interaction. The crystal structure at 2.9 angstrom resolution of ...
Nature structural & molecular biology, 2008
Nature Structural & Molecular Biology is an integrated forum for structural and molecular studies... more Nature Structural & Molecular Biology is an integrated forum for structural and molecular studies. The journal places a strong emphasis on functional and mechanistic understanding of how molecular components in a biological process work together. Structural data may provide ...