The Experts below are selected from a list of 222 Experts worldwide ranked by ideXlab platform
Suzana K. Straus - One of the best experts on this subject based on the ideXlab platform.
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Interactions of U24 from Roseolovirus with WW domains: canonical vs noncanonical.
Biochemistry and Cell Biology, 2017Co-Authors: Yurou Sang, Rui Zhang, A. Louise Creagh, Charles A. Haynes, Suzana K. StrausAbstract:U24 is a C-terminal membrane-anchored protein found in both human herpes virus type 6 and 7 (HHV-6 and HHV-7), with an N-terminal segment that is rich in prolines (PPxY motif in both HHV-6A and 7; PxxP motif in HHV-6A). Previous work has shown that U24 interacts strongly with Nedd4 WW domains, in particular, hNedd4L-WW3*. It was also shown that this interaction depends strongly on the nature of the amino acids that are upstream from the PY motif in U24. In this contribution, data was obtained from pull-downs, isothermal titration calorimetry, and NMR to further determine what modulates U24:WW domain interactions. Specifically, 3 non-canonical WW domains from human Smad ubiquitination regulatory factor (Smurf), namely hSmurf2-WW2, hSmurf2-WW3, and a tandem construct hSmurf2-WW2 + 3, were studied. Overall, the interactions between U24 and these Smurf WW domains were found to be weaker than those in U24:Nedd4 WW domain pairs, suggesting that U24 function is tightly linked to specific E3 ubiqitin ligases.
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U24 from Roseolovirus interacts strongly with Nedd4 WW Domains
Scientific Reports, 2017Co-Authors: Yurou Sang, Rui Zhang, Walter R. P. Scott, A. Louise Creagh, Charles A. Haynes, Suzana K. StrausAbstract:U24 is a protein found in both Roseoloviruses Human Herpes Virus type 6 and 7 (HHV-6 and HHV-7), with an N-terminus that is rich in prolines (PY motif in both HHV-6A and 7; PxxP motif in HHV-6A). Previous work has shown that the interaction between U24 and WW domains is important for endocytic recycling of T-cell receptors, but a cognate ligand was never identified. In this contribution, data was obtained from pull-downs, ITC, NMR and molecular dynamics simulations to show that a specific interaction exists between U24 and Nedd4 WW domains. ITC experiments were also carried out for U24 from HHV-6A phosphorylated at Thr6 (pU24-6A) and a peptide containing the PY motif from Nogo-A, a protein implicated in both the initial inflammatory and the neurodegenerative phases of multiple sclerosis (MS). The results suggest that phosphorylation of U24 from HHV-6A may be crucial for its potential role in MS.
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Probing the Interactions Between U24 from HHV-6A/7 and Fyn-SH3 or WW Domain Proteins
Biophysical Journal, 2014Co-Authors: Yurou Sang, Rui Zhang, Suzana K. StrausAbstract:U24 is a type II tail-anchored putative membrane protein unique to the Roseolovirus family, including HHV-6 and HHV-7. It contains an N-terminal proline-rich region and is believed to function by disrupting the signalling pathway in order to ensure the virus' survival. HHV-6A is a neurovirulent virus as it is often found in multiple sclerosis (MS) patients. It has also been shown to directly induce demyelination, a typical MS symptom, in naive adult marmosets1. U24 from HHV-6A shares a seven residue identity with myelin basic protein (MBP), a protein responsible for the compaction of the myelin sheath in the CNS2. U24 from HHV-7, on the other hand, does not share this sequence identity with MBP, but this virus has also been implicated in MS, though indirectly3.In order to elucidate the exact role of U24 in MS, we have investigated the interaction of this protein with other partners such as the SH3 domain from Fyn tyrosine kinase and WW domain proteins. GST pull-downs, NMR titration data and molecular dynamics simulations will be presented. The differences in binding observed for U24 from HHV-6A and -7 will shed light into the hypothesis that U24 may function by mimicking MBP, as it has been previously shown that U24 and MBP can be phosphorylated in a similar manner4.References1. Genain, C. (2006). US 2006/0130161 A1.2. Harauz, G., Ladizhansky, V., and Boggs, J.M. (2009). Biochemistry 48, 8094–8104.3. Sullivan, B.M., and Coscoy, L. (2010). Journal of Virology 84, 1265–1275.4. Tait, A.R., and Straus, S.K. (2008). FEBS Letters 582, 2685–2688.
Philip E. Pellett - One of the best experts on this subject based on the ideXlab platform.
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Roseolovirus molecular biology: recent advances
Current opinion in virology, 2014Co-Authors: Laurie T. Krug, Philip E. PellettAbstract:Human herpesviruses 6A, 6B, and 7 (HHV-6A, HHV-6B, and HHV-7) are classified within the Roseolovirus genus of the betaherpesvirus subfamily. Most humans likely harbor at least two of these large DNA viruses, and 1% of humans harbor germline chromosomally integrated (ci) HHV-6A or HHV-6B genomes. Differences at the genetic level manifest as distinct biologic properties during infection and disease. We provide a brief synopsis of Roseolovirus replication and highlight the unique properties of their lifecycle and what is known about the viral gene products that mediate these functions. In the nearly 30 years since their discovery, we have only begun to unlock the molecular strategies these highly evolved pathogens employ to establish and maintain chronic infections in humans.
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Differences in DNA binding specificity among Roseolovirus origin binding proteins.
Virology, 2001Co-Authors: Laurie T. Krug, Naoki Inoue, Philip E. PellettAbstract:Abstract The Roseolovirus genus of the Betaherpesvirinae consists of the very closely related viruses, human herpesvirus 6 variants A and B (HHV-6A and HHV-6B) plus the somewhat more distantly related human herpesvirus 7 (HHV-7). The Roseoloviruses each encode a homolog of the alphaherpesvirus origin binding protein (OBP) which is required for lytic DNA replication. In contrast, members of the other betaherpesvirus genera, the cytomegaloviruses, initiate DNA replication by a different mechanism. To better understand the basis of Roseolovirus OBP sequence specificity, we investigated their ability to recognize each other's binding sites. HHV-6A OBP (OBP H6A ) and HHV-6B OBP (OBP H6B ) each bind to both of the HHV-7 OBP sites (OBP-1 and OBP-2) with similar strengths, which are also similar to their nearly equivalent interactions with their own sites. In contrast, HHV-7 OBP (OBP H7 ) had a gradient of binding preferences: HHV-7 OBP-2 > HHV-6 OBP-2 > HHV-7 OBP-1 > HHV-6 OBP-1. Thus, the Roseolovirus OBPs are not equally reciprocal in their recognition of each other's OBP sites, suggesting that the sequence requirements for the interaction of OBPH7 at the OBP sites in its cognate ori Lyt differ from those of OBPH6A and OBPH6B.
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Sequence requirements for interaction of human herpesvirus 7 origin binding protein with the origin of lytic replication.
Journal of virology, 2001Co-Authors: Laurie T. Krug, Naoki Inoue, Philip E. PellettAbstract:As do human herpesvirus 6 variants A and B (HHV-6A and -6B), HHV-7 encodes a homolog of the alphaherpesvirus origin binding protein (OBP), which binds at sites in the origin of lytic replication (oriLyt) to initiate DNA replication. In this study, we sought to characterize the interaction of the HHV-7 OBP (OBPH7) with its cognate sites in the 600-bp HHV-7 oriLyt. We expressed the carboxyl-terminal domain of OBPH7 and found that amino acids 484 to 787 of OBPH7 were sufficient for DNA binding activity by electrophoretic mobility shift analysis. OBPH7 has one high-affinity binding site (OBP-2) located on one flank of an AT-rich spacer element and a low-affinity site (OBP-1) on the other. This is in contrast to the HHV-6B OBP (OBPH6B), which binds with similar affinity to its two cognate OBP sites in the HHV-6B oriLyt. The minimal recognition element of the OBP-2 site was mapped to a 14-bp sequence. The OBPH7 consensus recognition sequence of the 9-bp core, BRTYCWCCT (where B is a T, G, or C; R is a G or A; Y is a T or C; and W is a T or A), overlaps with the OBPH6B consensus YGWYCWCCY and establishes YCWCC as the Roseolovirus OBP core recognition sequence. Heteroduplex analysis suggests that OBPH7 interacts along one face of the DNA helix, with the major groove, as do OBPH6B and herpes simplex virus type 1 OBP. Together, these results illustrate both conserved and divergent DNA binding properties between OBPH7 and OBPH6B.
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Human Herpesviruses 6, 7, and 8
Reviews in Medical Microbiology, 2000Co-Authors: Sheila C. Dollard, Philip E. PellettAbstract:Human herpesviruses 6A and 6B (HHV-6A and HHV-6B) and human herpesvirus 7 (HHV-7) are viruses of the Roseolovirus genus in the betaherpesvirus subfamily, along with human cytomegalovirus. Roseoloviruses share many features of their genomic architecture and genetic content and the ability to replicate and establish latent infections in lymphocytes. Clinically, they cause febrile rash illnesses in young children and are associated with a variety of neurologic disorders. They are opportunistic pathogens in immunocompromised patients. HHV-6A has been identified during early-life febrile disease in Africa and in Hashimoto’s thyroiditis; its clinical spectrum remains to be fully defined. HHV-6B is the main cause of roseola and related febrile rash illnesses in young children and is often active during posttransplant acute limbic encephalitis. HHV-7 causes a subset of roseola cases, and along with HHV-6B, has been identified in children with febrile status epilepticus. Human herpesvirus 8 (HHV-8), or Kaposi’s sarcoma-associated herpesvirus, belongs to the gammaherpesvirus subfamily (as does Epstein-Barr virus). HHV-8 causes Kaposi’s sarcoma, multicentric Castleman’s disease, and primary effusion lymphoma, all of which are more likely to occur in HHV-8-seropositive individuals who are immunocompromised. Diagnosis of these viruses most often involves detection of their genomes by PCR, complemented by immunohistochemistry. Roseolovirus diagnosis is most often employed in the context of acute neurologic illnesses in young children and in organ and hematopoietic stem cell transplant recipients. HHV-8 diagnosis is employed in distinguishing Kaposi’s sarcoma from its mimickers and for definitive diagnosis of its associated lymphoproliferative disorders.
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human herpesvirus 6
Clinical Microbiology Reviews, 1997Co-Authors: Daniel K Braun, Geraldina Dominguez, Philip E. PellettAbstract:Human herpesvirus 6 variant A (HHV-6A) and human herpesvirus 6 variant B (HHV-6B) are two closely related yet distinct viruses. These visuses belong to the Roseolovirus genus of the betaherpesvirus subfamily; they are most closely related to human herpesvirus 7 and then to human cytomegalovirus. Over 95% of people older than 2 years of age are seropositive for either or both HHV-6 variants, and current serologic methods are incapable of discriminating infection with one variant from infection with the other. HHV-6A has not been etiologically linked to any human disease, but such an association will probably be found soon. HHV-6B is the etiologic agent of the common childhood illness exanthem subitum (roseola infantum or sixth disease) and related febrile illnesses. These viruses are frequently active and associated with illness in immunocompromised patients and may play a role in the etiology of Hodgkin's disease and other malignancies. HHV-6 is a commensal inhabitant of brains; various neurologic manifestations, including convulsions and encephalitis, can occur during primary HHV-6 infection or in immunocompromised patients. HHV-6 and distribution in the central nervous system are altered in patients with multiple sclerosis; the significance of this is under investigation.
Yurou Sang - One of the best experts on this subject based on the ideXlab platform.
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Interactions of U24 from Roseolovirus with WW domains: canonical vs noncanonical.
Biochemistry and Cell Biology, 2017Co-Authors: Yurou Sang, Rui Zhang, A. Louise Creagh, Charles A. Haynes, Suzana K. StrausAbstract:U24 is a C-terminal membrane-anchored protein found in both human herpes virus type 6 and 7 (HHV-6 and HHV-7), with an N-terminal segment that is rich in prolines (PPxY motif in both HHV-6A and 7; PxxP motif in HHV-6A). Previous work has shown that U24 interacts strongly with Nedd4 WW domains, in particular, hNedd4L-WW3*. It was also shown that this interaction depends strongly on the nature of the amino acids that are upstream from the PY motif in U24. In this contribution, data was obtained from pull-downs, isothermal titration calorimetry, and NMR to further determine what modulates U24:WW domain interactions. Specifically, 3 non-canonical WW domains from human Smad ubiquitination regulatory factor (Smurf), namely hSmurf2-WW2, hSmurf2-WW3, and a tandem construct hSmurf2-WW2 + 3, were studied. Overall, the interactions between U24 and these Smurf WW domains were found to be weaker than those in U24:Nedd4 WW domain pairs, suggesting that U24 function is tightly linked to specific E3 ubiqitin ligases.
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U24 from Roseolovirus interacts strongly with Nedd4 WW Domains
Scientific Reports, 2017Co-Authors: Yurou Sang, Rui Zhang, Walter R. P. Scott, A. Louise Creagh, Charles A. Haynes, Suzana K. StrausAbstract:U24 is a protein found in both Roseoloviruses Human Herpes Virus type 6 and 7 (HHV-6 and HHV-7), with an N-terminus that is rich in prolines (PY motif in both HHV-6A and 7; PxxP motif in HHV-6A). Previous work has shown that the interaction between U24 and WW domains is important for endocytic recycling of T-cell receptors, but a cognate ligand was never identified. In this contribution, data was obtained from pull-downs, ITC, NMR and molecular dynamics simulations to show that a specific interaction exists between U24 and Nedd4 WW domains. ITC experiments were also carried out for U24 from HHV-6A phosphorylated at Thr6 (pU24-6A) and a peptide containing the PY motif from Nogo-A, a protein implicated in both the initial inflammatory and the neurodegenerative phases of multiple sclerosis (MS). The results suggest that phosphorylation of U24 from HHV-6A may be crucial for its potential role in MS.
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Probing the Interactions Between U24 from HHV-6A/7 and Fyn-SH3 or WW Domain Proteins
Biophysical Journal, 2014Co-Authors: Yurou Sang, Rui Zhang, Suzana K. StrausAbstract:U24 is a type II tail-anchored putative membrane protein unique to the Roseolovirus family, including HHV-6 and HHV-7. It contains an N-terminal proline-rich region and is believed to function by disrupting the signalling pathway in order to ensure the virus' survival. HHV-6A is a neurovirulent virus as it is often found in multiple sclerosis (MS) patients. It has also been shown to directly induce demyelination, a typical MS symptom, in naive adult marmosets1. U24 from HHV-6A shares a seven residue identity with myelin basic protein (MBP), a protein responsible for the compaction of the myelin sheath in the CNS2. U24 from HHV-7, on the other hand, does not share this sequence identity with MBP, but this virus has also been implicated in MS, though indirectly3.In order to elucidate the exact role of U24 in MS, we have investigated the interaction of this protein with other partners such as the SH3 domain from Fyn tyrosine kinase and WW domain proteins. GST pull-downs, NMR titration data and molecular dynamics simulations will be presented. The differences in binding observed for U24 from HHV-6A and -7 will shed light into the hypothesis that U24 may function by mimicking MBP, as it has been previously shown that U24 and MBP can be phosphorylated in a similar manner4.References1. Genain, C. (2006). US 2006/0130161 A1.2. Harauz, G., Ladizhansky, V., and Boggs, J.M. (2009). Biochemistry 48, 8094–8104.3. Sullivan, B.M., and Coscoy, L. (2010). Journal of Virology 84, 1265–1275.4. Tait, A.R., and Straus, S.K. (2008). FEBS Letters 582, 2685–2688.
Rui Zhang - One of the best experts on this subject based on the ideXlab platform.
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Interactions of U24 from Roseolovirus with WW domains: canonical vs noncanonical.
Biochemistry and Cell Biology, 2017Co-Authors: Yurou Sang, Rui Zhang, A. Louise Creagh, Charles A. Haynes, Suzana K. StrausAbstract:U24 is a C-terminal membrane-anchored protein found in both human herpes virus type 6 and 7 (HHV-6 and HHV-7), with an N-terminal segment that is rich in prolines (PPxY motif in both HHV-6A and 7; PxxP motif in HHV-6A). Previous work has shown that U24 interacts strongly with Nedd4 WW domains, in particular, hNedd4L-WW3*. It was also shown that this interaction depends strongly on the nature of the amino acids that are upstream from the PY motif in U24. In this contribution, data was obtained from pull-downs, isothermal titration calorimetry, and NMR to further determine what modulates U24:WW domain interactions. Specifically, 3 non-canonical WW domains from human Smad ubiquitination regulatory factor (Smurf), namely hSmurf2-WW2, hSmurf2-WW3, and a tandem construct hSmurf2-WW2 + 3, were studied. Overall, the interactions between U24 and these Smurf WW domains were found to be weaker than those in U24:Nedd4 WW domain pairs, suggesting that U24 function is tightly linked to specific E3 ubiqitin ligases.
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U24 from Roseolovirus interacts strongly with Nedd4 WW Domains
Scientific Reports, 2017Co-Authors: Yurou Sang, Rui Zhang, Walter R. P. Scott, A. Louise Creagh, Charles A. Haynes, Suzana K. StrausAbstract:U24 is a protein found in both Roseoloviruses Human Herpes Virus type 6 and 7 (HHV-6 and HHV-7), with an N-terminus that is rich in prolines (PY motif in both HHV-6A and 7; PxxP motif in HHV-6A). Previous work has shown that the interaction between U24 and WW domains is important for endocytic recycling of T-cell receptors, but a cognate ligand was never identified. In this contribution, data was obtained from pull-downs, ITC, NMR and molecular dynamics simulations to show that a specific interaction exists between U24 and Nedd4 WW domains. ITC experiments were also carried out for U24 from HHV-6A phosphorylated at Thr6 (pU24-6A) and a peptide containing the PY motif from Nogo-A, a protein implicated in both the initial inflammatory and the neurodegenerative phases of multiple sclerosis (MS). The results suggest that phosphorylation of U24 from HHV-6A may be crucial for its potential role in MS.
-
Probing the Interactions Between U24 from HHV-6A/7 and Fyn-SH3 or WW Domain Proteins
Biophysical Journal, 2014Co-Authors: Yurou Sang, Rui Zhang, Suzana K. StrausAbstract:U24 is a type II tail-anchored putative membrane protein unique to the Roseolovirus family, including HHV-6 and HHV-7. It contains an N-terminal proline-rich region and is believed to function by disrupting the signalling pathway in order to ensure the virus' survival. HHV-6A is a neurovirulent virus as it is often found in multiple sclerosis (MS) patients. It has also been shown to directly induce demyelination, a typical MS symptom, in naive adult marmosets1. U24 from HHV-6A shares a seven residue identity with myelin basic protein (MBP), a protein responsible for the compaction of the myelin sheath in the CNS2. U24 from HHV-7, on the other hand, does not share this sequence identity with MBP, but this virus has also been implicated in MS, though indirectly3.In order to elucidate the exact role of U24 in MS, we have investigated the interaction of this protein with other partners such as the SH3 domain from Fyn tyrosine kinase and WW domain proteins. GST pull-downs, NMR titration data and molecular dynamics simulations will be presented. The differences in binding observed for U24 from HHV-6A and -7 will shed light into the hypothesis that U24 may function by mimicking MBP, as it has been previously shown that U24 and MBP can be phosphorylated in a similar manner4.References1. Genain, C. (2006). US 2006/0130161 A1.2. Harauz, G., Ladizhansky, V., and Boggs, J.M. (2009). Biochemistry 48, 8094–8104.3. Sullivan, B.M., and Coscoy, L. (2010). Journal of Virology 84, 1265–1275.4. Tait, A.R., and Straus, S.K. (2008). FEBS Letters 582, 2685–2688.
Laurie T. Krug - One of the best experts on this subject based on the ideXlab platform.
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Roseolovirus molecular biology: recent advances
Current opinion in virology, 2014Co-Authors: Laurie T. Krug, Philip E. PellettAbstract:Human herpesviruses 6A, 6B, and 7 (HHV-6A, HHV-6B, and HHV-7) are classified within the Roseolovirus genus of the betaherpesvirus subfamily. Most humans likely harbor at least two of these large DNA viruses, and 1% of humans harbor germline chromosomally integrated (ci) HHV-6A or HHV-6B genomes. Differences at the genetic level manifest as distinct biologic properties during infection and disease. We provide a brief synopsis of Roseolovirus replication and highlight the unique properties of their lifecycle and what is known about the viral gene products that mediate these functions. In the nearly 30 years since their discovery, we have only begun to unlock the molecular strategies these highly evolved pathogens employ to establish and maintain chronic infections in humans.
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Differences in DNA binding specificity among Roseolovirus origin binding proteins.
Virology, 2001Co-Authors: Laurie T. Krug, Naoki Inoue, Philip E. PellettAbstract:Abstract The Roseolovirus genus of the Betaherpesvirinae consists of the very closely related viruses, human herpesvirus 6 variants A and B (HHV-6A and HHV-6B) plus the somewhat more distantly related human herpesvirus 7 (HHV-7). The Roseoloviruses each encode a homolog of the alphaherpesvirus origin binding protein (OBP) which is required for lytic DNA replication. In contrast, members of the other betaherpesvirus genera, the cytomegaloviruses, initiate DNA replication by a different mechanism. To better understand the basis of Roseolovirus OBP sequence specificity, we investigated their ability to recognize each other's binding sites. HHV-6A OBP (OBP H6A ) and HHV-6B OBP (OBP H6B ) each bind to both of the HHV-7 OBP sites (OBP-1 and OBP-2) with similar strengths, which are also similar to their nearly equivalent interactions with their own sites. In contrast, HHV-7 OBP (OBP H7 ) had a gradient of binding preferences: HHV-7 OBP-2 > HHV-6 OBP-2 > HHV-7 OBP-1 > HHV-6 OBP-1. Thus, the Roseolovirus OBPs are not equally reciprocal in their recognition of each other's OBP sites, suggesting that the sequence requirements for the interaction of OBPH7 at the OBP sites in its cognate ori Lyt differ from those of OBPH6A and OBPH6B.
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Sequence requirements for interaction of human herpesvirus 7 origin binding protein with the origin of lytic replication.
Journal of virology, 2001Co-Authors: Laurie T. Krug, Naoki Inoue, Philip E. PellettAbstract:As do human herpesvirus 6 variants A and B (HHV-6A and -6B), HHV-7 encodes a homolog of the alphaherpesvirus origin binding protein (OBP), which binds at sites in the origin of lytic replication (oriLyt) to initiate DNA replication. In this study, we sought to characterize the interaction of the HHV-7 OBP (OBPH7) with its cognate sites in the 600-bp HHV-7 oriLyt. We expressed the carboxyl-terminal domain of OBPH7 and found that amino acids 484 to 787 of OBPH7 were sufficient for DNA binding activity by electrophoretic mobility shift analysis. OBPH7 has one high-affinity binding site (OBP-2) located on one flank of an AT-rich spacer element and a low-affinity site (OBP-1) on the other. This is in contrast to the HHV-6B OBP (OBPH6B), which binds with similar affinity to its two cognate OBP sites in the HHV-6B oriLyt. The minimal recognition element of the OBP-2 site was mapped to a 14-bp sequence. The OBPH7 consensus recognition sequence of the 9-bp core, BRTYCWCCT (where B is a T, G, or C; R is a G or A; Y is a T or C; and W is a T or A), overlaps with the OBPH6B consensus YGWYCWCCY and establishes YCWCC as the Roseolovirus OBP core recognition sequence. Heteroduplex analysis suggests that OBPH7 interacts along one face of the DNA helix, with the major groove, as do OBPH6B and herpes simplex virus type 1 OBP. Together, these results illustrate both conserved and divergent DNA binding properties between OBPH7 and OBPH6B.
