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Article ; Online: Predicting binding sites from unbound versus bound protein structures.

Clark, Jordan J / Orban, Zachary J / Carlson, Heather A

2020 Volume 10, Issue 1, Page(s) 15856

Abstract: We present the application of seven binding-site prediction algorithms to a meticulously curated dataset of ligand-bound and ligand-free crystal structures for 304 unique protein sequences (2528 crystal structures). We probe the influence of starting ... ...

Abstract	We present the application of seven binding-site prediction algorithms to a meticulously curated dataset of ligand-bound and ligand-free crystal structures for 304 unique protein sequences (2528 crystal structures). We probe the influence of starting protein structures on the results of binding-site prediction, so the dataset contains a minimum of two ligand-bound and two ligand-free structures for each protein. We use this dataset in a brief survey of five geometry-based, one energy-based, and one machine-learning-based methods: Surfnet, Ghecom, LIGSITE
MeSH term(s)	Algorithms ; Apoproteins/chemistry ; Apoproteins/metabolism ; Binding Sites ; Computational Biology ; Databases, Protein ; Proteins/chemistry ; Proteins/metabolism
Chemical Substances	Apoproteins ; Proteins
Language	English
Publishing date	2020-09-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-72906-7
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Article ; Online: Virus-like particles of louping ill virus elicit potent neutralizing antibodies targeting multimers of viral envelope protein.

Tandavanitj, Rapeepat / Setthapramote, Chayanee / De Lorenzo, Giuditta / Sanchez-Velazquez, Ricardo / Clark, Jordan J / Rocchi, Mara / McInnes, Colin / Kohl, Alain / Patel, Arvind H

Vaccine

2024 Volume 42, Issue 9, Page(s) 2429–2437

Abstract: Louping ill virus (LIV) is a tick-borne flavivirus that predominantly causes disease in livestock, especially sheep in the British Isles. A preventive vaccine, previously approved for veterinary use but now discontinued, was based on an inactivated whole ...

Abstract	Louping ill virus (LIV) is a tick-borne flavivirus that predominantly causes disease in livestock, especially sheep in the British Isles. A preventive vaccine, previously approved for veterinary use but now discontinued, was based on an inactivated whole virion that likely provided protection by induction of neutralizing antibodies recognizing the viral envelope (E) protein. A major disadvantage of the inactivated vaccine was the need for high containment facilities for the propagation of infectious virus, as mandated by the hazard group 3 status of the virus. This study aimed to develop high-efficacy non-infectious protein-based vaccine candidates. Specifically, soluble envelope protein (sE), and virus-like particles (VLPs), comprised of the precursor of membrane and envelope proteins, were generated, characterized, and studied for their immunogenicity in mice. Results showed that the VLPs induced more potent virus neutralizing response compared to sE, even though the total anti-envelope IgG content induced by the two antigens was similar. Depletion of anti-monomeric E protein antibodies from mouse immune sera suggested that the neutralizing antibodies elicited by the VLPs targeted epitopes spanning the highly organized structure of multimer of the E protein, whereas the antibody response induced by sE focused on E monomers. Thus, our results indicate that VLPs represent a promising LIV vaccine candidate.
MeSH term(s)	Animals ; Mice ; Sheep ; Antibodies, Neutralizing ; Encephalitis Viruses, Tick-Borne ; Antibodies, Viral ; Viral Envelope Proteins ; Vaccines ; Vaccines, Virus-Like Particle
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Viral Envelope Proteins ; Vaccines ; Vaccines, Virus-Like Particle
Language	English
Publishing date	2024-03-08
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2024.03.008
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Article ; Online: Inherent versus induced protein flexibility: Comparisons within and between apo and holo structures.

Clark, Jordan J / Benson, Mark L / Smith, Richard D / Carlson, Heather A

PLoS computational biology

2019 Volume 15, Issue 1, Page(s) e1006705

Abstract: Understanding how ligand binding influences protein flexibility is important, especially in rational drug design. Protein flexibility upon ligand binding is analyzed herein using 305 proteins with 2369 crystal structures with ligands (holo) and 1679 ... ...

Abstract	Understanding how ligand binding influences protein flexibility is important, especially in rational drug design. Protein flexibility upon ligand binding is analyzed herein using 305 proteins with 2369 crystal structures with ligands (holo) and 1679 without (apo). Each protein has at least two apo and two holo structures for analysis. The inherent variation in structures with and without ligands is first established as a baseline. This baseline is then compared to the change in conformation in going from the apo to holo states to probe induced flexibility. The inherent backbone flexibility across the apo structures is roughly the same as the variation across holo structures. The induced backbone flexibility across apo-holo pairs is larger than that of the apo or holo states, but the increase in RMSD is less than 0.5 Å. Analysis of χ1 angles revealed a distinctly different pattern with significant influences seen for ligand binding on side-chain conformations in the binding site. Within the apo and holo states themselves, the variation of the χ1 angles is the same. However, the data combining both apo and holo states show significant displacements. Upon ligand binding, χ1 angles are frequently pushed to new orientations outside the range seen in the apo states. Influences on binding-site variation could not be easily attributed to features such as ligand size or x-ray structure resolution. By combining these findings, we find that most binding site flexibility is compatible with the common practice in flexible docking, where backbones are kept rigid and side chains are allowed some degree of flexibility.
MeSH term(s)	Crystallography, X-Ray ; Databases, Protein ; Ligands ; Pliability/physiology ; Protein Binding ; Protein Conformation ; Proteins/chemistry ; Proteins/metabolism
Chemical Substances	Ligands ; Proteins
Language	English
Publishing date	2019-01-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1006705
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Article ; Online: The Stereotypic Response of the Pulmonary Vasculature to Respiratory Viral Infections: Findings in Mouse Models of SARS-CoV-2, Influenza A and Gammaherpesvirus Infections.

De Neck, Simon / Penrice-Randal, Rebekah / Clark, Jordan J / Sharma, Parul / Bentley, Eleanor G / Kirby, Adam / Mega, Daniele F / Han, Ximeng / Owen, Andrew / Hiscox, Julian A / Stewart, James P / Kipar, Anja

Viruses

2023 Volume 15, Issue 8

Abstract: The respiratory system is the main target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 19 (COVID-19) where acute respiratory distress syndrome is considered the leading cause of death. Changes in ... ...

Abstract	The respiratory system is the main target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 19 (COVID-19) where acute respiratory distress syndrome is considered the leading cause of death. Changes in pulmonary blood vessels, among which an endothelialitis/endotheliitis has been particularly emphasized, have been suggested to play a central role in the development of acute lung injury. Similar vascular changes are also observed in animal models of COVID-19. The present study aimed to determine whether the latter are specific for SARS-CoV-2 infection, investigating the vascular response in the lungs of mice infected with SARS-CoV-2 and other respiratory viruses (influenza A and murine gammaherpesvirus) by in situ approaches (histology, immunohistology, morphometry) combined with RNA sequencing and bioinformatic analysis. Non-selective recruitment of monocytes and T and B cells from larger muscular veins and arteries was observed with all viruses, matched by a comparable transcriptional response. There was no evidence of endothelial cell infection in any of the models. Both the morphological investigation and the transcriptomics approach support the interpretation that the lung vasculature in mice mounts a stereotypic response to alveolar and respiratory epithelial damage. This may have implications for the treatment and management of respiratory disease in humans.
MeSH term(s)	Humans ; Animals ; Mice ; Influenza, Human ; SARS-CoV-2 ; COVID-19 ; Cardiovascular System ; Disease Models, Animal ; Gammaherpesvirinae
Language	English
Publishing date	2023-07-27
Publishing country	Switzerland
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v15081637
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Article ; Online: Inhibition of type I interferon induction and signalling by mosquito-borne flaviviruses.

Cumberworth, Stephanie L / Clark, Jordan J / Kohl, Alain / Donald, Claire L

Cellular microbiology

2017 Volume 19, Issue 5

Abstract: The Flavivirus genus (Flaviviridae family) contains a number of important human pathogens, including dengue and Zika viruses, which have the potential to cause severe disease. In order to efficiently establish a productive infection in mammalian cells, ... ...

Abstract	The Flavivirus genus (Flaviviridae family) contains a number of important human pathogens, including dengue and Zika viruses, which have the potential to cause severe disease. In order to efficiently establish a productive infection in mammalian cells, flaviviruses have developed key strategies to counteract host immune defences, including the type I interferon response. They employ different mechanisms to control interferon signal transduction and effector pathways, and key research generated over the past couple of decades has uncovered new insights into their abilities to actively decrease interferon antiviral activity. Given the lack of antivirals or prophylactic treatments for many flaviviral infections, it is important to fully understand how these viruses affect cellular processes to influence pathogenesis and disease outcome. This review will discuss the strategies mosquito-borne flaviviruses have evolved to antagonise type I interferon mediated immune responses.
MeSH term(s)	Animals ; Culicidae/virology ; Flavivirus/physiology ; Flavivirus Infections/immunology ; Flavivirus Infections/virology ; Host-Pathogen Interactions ; Humans ; Immunity, Innate ; Insect Vectors/virology ; Interferon Type I/genetics ; Interferon Type I/metabolism ; Transcriptional Activation/immunology ; Viral Nonstructural Proteins/physiology
Chemical Substances	Interferon Type I ; Viral Nonstructural Proteins
Language	English
Publishing date	2017-03-22
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1468320-9
ISSN	1462-5822 ; 1462-5814
ISSN (online)	1462-5822
ISSN	1462-5814
DOI	10.1111/cmi.12737
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Article ; Online: Amino acids 1811-1960 of myosin heavy chain 9 is involved in murine gammaherpesvirus 68 infection.

Han, Ximeng / Clark, Jordan J / Sharma, Parul / Bentley, Eleanor G / Kipar, Anja / Alsayer, Mohammed / Ren, Xiaolei / Robinson, Amy / Alaidarous, Sondus / Mu, Yang / Sun, Yani / Hiscox, Julian A / Zhou, En-Min / Stewart, James P / Zhao, Qin

Virology

2023 Volume 587, Page(s) 109849

Abstract: Myosin heavy chain 9 (MYH9) has been identified as a crucial factor in gammaherpesvirus infection. Murine gammaherpesvirus 68 (MHV-68) was used as an appropriate viral model for investigating gammaherpesviruses in vivo and developing antiviral treatments. ...

Abstract	Myosin heavy chain 9 (MYH9) has been identified as a crucial factor in gammaherpesvirus infection. Murine gammaherpesvirus 68 (MHV-68) was used as an appropriate viral model for investigating gammaherpesviruses in vivo and developing antiviral treatments. However, the roles of MYH9 in MHV-68 infection have not been documented. In the study, the relationship between the expression of MYH9 and MHV-68 infection and MYH9 as the antiviral target were analyzed. The results revealed that MYH9 was enriched on the cell surface and co-localized with MHV-68 upon viral infection. Knocking down MYH9 with siRNA or using the specific inhibitor of MYH9 activity, Blebbistatin, resulted in the decreasing of MHV-68 infection. Furthermore, polyclonal antibodies against MYH9 reduced infection by approximately 74% at a dose of 100 μg/ml. The study determined that MYH9 contributes to MHV-68 infection by interacting with viral glycoprotein 150 (gp150) in the BHK-21 cell membrane. The specific region of MYH9, amino acids 1811-1960 (C-150), was identified as the key domain involved in the interaction with MHV-68 gp150 and was found to inhibit MHV-68 infection. Moreover, C-150 was also shown to decrease HSV-1 infection in Vero cells by approximately 73%. Both C-150 and Blebbistatin were found to inhibit MHV-68 replication and reduce histopathological lesions in vivo in C57BL/6J mice. Taken together, these findings suggested that MYH9 is crucial for MHV-68 infection through its interaction with viral gp150 and that C-150 may be a promising antiviral target for inhibiting MHV-68 infection in vitro and in vivo.
MeSH term(s)	Animals ; Mice ; Amino Acids ; Antiviral Agents/metabolism ; Chlorocebus aethiops ; Gammaherpesvirinae/genetics ; Herpesviridae Infections ; Mice, Inbred C57BL ; Myosin Heavy Chains/genetics ; Myosin Heavy Chains/metabolism ; Rhadinovirus/genetics ; Vero Cells ; Viral Proteins/genetics ; Viral Proteins/metabolism
Chemical Substances	Amino Acids ; Antiviral Agents ; Myosin Heavy Chains (EC 3.6.4.1) ; Viral Proteins ; Myh9 protein, mouse
Language	English
Publishing date	2023-07-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2023.109849
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Article: Updates to Binding MOAD (Mother of All Databases): Polypharmacology Tools and Their Utility in Drug Repurposing

Smith, Richard D / Clark, Jordan J / Ahmed, Aqeel / Orban, Zachary J / Dunbar, James B / Carlson, Heather A

Journal of molecular biology. 2019 June 14, v. 431, no. 13

2019

Abstract: The goal of Binding MOAD is to provide users with a data set focused on high-quality x-ray crystal structures that have been solved with biologically relevant ligands bound. Where available, experimental binding affinities (Ka, Kd, Ki, IC50) are provided ...

Abstract	The goal of Binding MOAD is to provide users with a data set focused on high-quality x-ray crystal structures that have been solved with biologically relevant ligands bound. Where available, experimental binding affinities (Ka, Kd, Ki, IC50) are provided from the primary literature of the crystal structure. The database has been updated regularly since 2005, and this most recent update has added nearly 7000 new structures (growth of 21%). MOAD currently contains 32,747 structures, composed of 9117 protein families and 16,044 unique ligands. The data are freely available on www.BindingMOAD.org. This paper outlines updates to the data in Binding MOAD as well as improvements made to both the website and its contents. The NGL viewer has been added to improve visualization of the ligands and protein structures. MarvinJS has been implemented, over the outdated MarvinView, to work with JChem for small molecule searching in the database. To add tools for predicting polypharmacology, we have added information about sequence, binding-site, and ligand similarity between entries in the database. A main premise behind polypharmacology is that similar binding sites will bind similar ligands. The large amount of protein–ligand information available in Binding MOAD allows us to compute pairwise ligand and binding-site similarities. Lists of similar ligands and similar binding sites have been added to allow users to identify potential polypharmacology pairs. To show the utility of the polypharmacology data, we detail a few examples from Binding MOAD of drug repurposing targets with their respective similarities.
Keywords	Internet ; binding capacity ; binding sites ; crystal structure ; data collection ; databases ; drugs ; inhibitory concentration 50 ; ligands ; prediction ; protein structure
Language	English
Dates of publication	2019-0614
Size	p. 2423-2433.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2019.05.024
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Neuroinvasion and Neurotropism by SARS-CoV-2 Variants in the K18-hACE2 Mouse.

Seehusen, Frauke / Clark, Jordan J / Sharma, Parul / Bentley, Eleanor G / Kirby, Adam / Subramaniam, Krishanthi / Wunderlin-Giuliani, Sabina / Hughes, Grant L / Patterson, Edward I / Michael, Benedict D / Owen, Andrew / Hiscox, Julian A / Stewart, James P / Kipar, Anja

Viruses

2022 Volume 14, Issue 5

Abstract: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) not only affects the respiratory tract but also causes neurological symptoms such as loss of smell and taste, headache, fatigue or severe cerebrovascular complications. Using transgenic mice ... ...

Abstract	Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) not only affects the respiratory tract but also causes neurological symptoms such as loss of smell and taste, headache, fatigue or severe cerebrovascular complications. Using transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2), we investigated the spatiotemporal distribution and pathomorphological features in the CNS following intranasal infection with SARS-CoV-2 variants, as well as after prior influenza A virus infection. Apart from Omicron, we found all variants to frequently spread to and within the CNS. Infection was restricted to neurons and appeared to spread from the olfactory bulb mainly in basally oriented regions in the brain and into the spinal cord, independent of ACE2 expression and without evidence of neuronal cell death, axonal damage or demyelination. However, microglial activation, microgliosis and a mild macrophage and T cell dominated inflammatory response was consistently observed, accompanied by apoptotic death of endothelial, microglial and immune cells, without their apparent infection. Microgliosis and immune cell apoptosis indicate a potential role of microglia for pathogenesis and viral effect in COVID-19 and the possible impairment of neurological functions, especially in long COVID. These data may also be informative for the selection of therapeutic candidates and broadly support the investigation of agents with adequate penetration into relevant regions of the CNS.
MeSH term(s)	Angiotensin-Converting Enzyme 2/genetics ; Animals ; COVID-19/complications ; Central Nervous System/physiopathology ; Central Nervous System/virology ; Humans ; Mice ; Mice, Transgenic ; SARS-CoV-2/genetics ; Viral Tropism ; Post-Acute COVID-19 Syndrome
Chemical Substances	ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2022-05-11
Publishing country	Switzerland
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v14051020
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Article ; Online: Updates to Binding MOAD (Mother of All Databases): Polypharmacology Tools and Their Utility in Drug Repurposing.

Smith, Richard D / Clark, Jordan J / Ahmed, Aqeel / Orban, Zachary J / Dunbar, James B / Carlson, Heather A

Journal of molecular biology

2019 Volume 431, Issue 13, Page(s) 2423–2433

Abstract	The goal of Binding MOAD is to provide users with a data set focused on high-quality x-ray crystal structures that have been solved with biologically relevant ligands bound. Where available, experimental binding affinities (K
MeSH term(s)	Binding Sites ; Crystallography, X-Ray ; Databases, Protein ; Drug Repositioning ; Polypharmacology ; Proteins/chemistry
Chemical Substances	Proteins
Language	English
Publishing date	2019-05-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2019.05.024
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Article ; Online: The IRE1α-XBP1 arm of the unfolded protein response is a host factor activated in SARS-CoV-2 infection.

Fernández, Jose Javier / Marín, Arturo / Rosales, Romel / Penrice-Randal, Rebekah / Mlcochova, Petra / Alvarez, Yolanda / Villalón-Letelier, Fernando / Yildiz, Soner / Pérez, Enrique / Rathnasinghe, Raveen / Cupic, Anastasija / Kehrer, Thomas / Uccellini, Melissa B / Alonso, Sara / Martínez, Fernando / McGovern, Briana Lynn / Clark, Jordan J / Sharma, Parul / Bayón, Yolanda /

Alonso, Andrés / Albrecht, Randy A / White, Kris M / Schotsaert, Michael / Miorin, Lisa / Stewart, James P / Hiscox, Julian A / Gupta, Ravindra K / Irigoyen, Nerea / García-Sastre, Adolfo / Crespo, Mariano Sánchez / Fernández, Nieves

Biochimica et biophysica acta. Molecular basis of disease

2024 Volume 1870, Issue 5, Page(s) 167193

Abstract: SARS-CoV-2 infection can cause severe pneumonia, wherein exacerbated inflammation plays a major role. This is reminiscent of the process commonly termed cytokine storm, a condition dependent on a disproportionated production of cytokines. This state ... ...

Abstract	SARS-CoV-2 infection can cause severe pneumonia, wherein exacerbated inflammation plays a major role. This is reminiscent of the process commonly termed cytokine storm, a condition dependent on a disproportionated production of cytokines. This state involves the activation of the innate immune response by viral patterns and coincides with the biosynthesis of the biomass required for viral replication, which may overwhelm the capacity of the endoplasmic reticulum and drive the unfolded protein response (UPR). The UPR is a signal transduction pathway composed of three branches that is initiated by a set of sensors: inositol-requiring protein 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6). These sensors control adaptive processes, including the transcriptional regulation of proinflammatory cytokines. Based on this background, the role of the UPR in SARS-CoV-2 replication and the ensuing inflammatory response was investigated using in vivo and in vitro models of infection. Mice and Syrian hamsters infected with SARS-CoV-2 showed a sole activation of the Ire1α-Xbp1 arm of the UPR associated with a robust production of proinflammatory cytokines. Human lung epithelial cells showed the dependence of viral replication on the expression of UPR-target proteins branching on the IRE1α-XBP1 arm and to a lower extent on the PERK route. Likewise, activation of the IRE1α-XBP1 branch by Spike (S) proteins from different variants of concern was a uniform finding. These results show that the IRE1α-XBP1 system enhances viral replication and cytokine expression and may represent a potential therapeutic target in SARS-CoV-2 severe pneumonia.
Language	English
Publishing date	2024-04-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	60-7
ISSN	1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbadis.2024.167193
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