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Article ; Online: Binding Studies of the Prodrug HAO472 to SARS-Cov-2 Nsp9 and Variants.

Liu, Miaomiao / Littler, Dene R / Rossjohn, Jamie / Quinn, Ronald J

ACS omega

2022 Volume 7, Issue 8, Page(s) 7327–7332

Abstract: SARS-CoV-2 (COVID-19) has infected over 219 million people and caused the death of over 4.55 million worldwide. In a previous screen of a natural product library against purified SARS-CoV-2 Nsp9 using a native mass spectrometry-based approach, we ... ...

Abstract	SARS-CoV-2 (COVID-19) has infected over 219 million people and caused the death of over 4.55 million worldwide. In a previous screen of a natural product library against purified SARS-CoV-2 Nsp9 using a native mass spectrometry-based approach, we identified an
Language	English
Publishing date	2022-02-15
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.1c07186
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Inside-out: Antibody-binding reveals potential folding hinge-points within the SARS-CoV-2 replication co-factor nsp9.

Pan, Yue / Chandrashekaran, Indu R / Tennant, Luke / Rossjohn, Jamie / Littler, Dene R

PloS one

2023 Volume 18, Issue 4, Page(s) e0283194

Abstract: Nsp9 is a conserved accessory component of the coronaviral replication and transcription complex. It is the predominant substrate of nsp12's nucleotidylation activity while also serving to recruit proteins required for viral 5'-capping. Anti-nsp9 ... ...

Abstract	Nsp9 is a conserved accessory component of the coronaviral replication and transcription complex. It is the predominant substrate of nsp12's nucleotidylation activity while also serving to recruit proteins required for viral 5'-capping. Anti-nsp9 specific nanobodies have been isolated previously. We confirm that their binding mode is centred upon Trp-53 within SARS-CoV-2 nsp9. Antibody binding at this site surprisingly results in large-scale changes to the overall topology of this coronaviral unique fold. We further characterise the antibody-induced structural dynamism within nsp9, identifying a number of potentially flexible regions. A large expansion of the cavity between the s2-s3 and s4-s5 loops is particularly noteworthy. As is the potential for large-scale movements in the C-terminal GxxxG helix.
MeSH term(s)	Humans ; SARS-CoV-2/metabolism ; Viral Nonstructural Proteins/metabolism ; COVID-19
Chemical Substances	Viral Nonstructural Proteins
Language	English
Publishing date	2023-04-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0283194
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Discovery of Anti-SARS-CoV-2 Nsp9 Binders from Natural Products by a Native Mass Spectrometry Approach.

Quinn, Ronald J / Mak, Tin / Littler, Dene R / Rossjohn, Jamie / Liu, Miaomiao

Journal of natural products

2023 Volume 86, Issue 12, Page(s) 2630–2637

Abstract: The search for effective antiviral agents against SARS-CoV-2 remains a critical global endeavor. In this study, we focused on the viral nucleocapsid protein Nsp9, which is a key player in viral RNA replication and an attractive drug target. Employing a ... ...

Abstract	The search for effective antiviral agents against SARS-CoV-2 remains a critical global endeavor. In this study, we focused on the viral nucleocapsid protein Nsp9, which is a key player in viral RNA replication and an attractive drug target. Employing a two-pronged approach, an in-house natural product library was screened using native mass spectrometry to identify compounds capable of binding to Nsp9. From the initial screening, apart from the previously reported hit oridonin (protein binding ratio of 0.56 in the initial screening,
MeSH term(s)	Humans ; SARS-CoV-2 ; COVID-19 ; Diterpenes, Kaurane/pharmacology ; Protein Binding ; Antiviral Agents/pharmacology
Chemical Substances	oridonin (0APJ98UCLQ) ; Diterpenes, Kaurane ; Antiviral Agents
Language	English
Publishing date	2023-11-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	304325-3
ISSN	1520-6025 ; 0163-3864
ISSN (online)	1520-6025
ISSN	0163-3864
DOI	10.1021/acs.jnatprod.3c00636
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Zs.A 1144: Show issues

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Article ; Online: Collision-Induced Affinity Selection Mass Spectrometry for Identification of Ligands.

Mak, Tin / Rossjohn, Jamie / Littler, Dene R / Liu, Miaomiao / Quinn, Ronald J

ACS bio & med chem Au

2022 Volume 2, Issue 5, Page(s) 450–455

Abstract: Hyphenated mass spectrometry has been used to identify ligands binding to proteins. It involves mixing protein and compounds, separation of protein-ligand complexes from unbound compounds, dissociation of the protein-ligand complex, separation to remove ... ...

Abstract	Hyphenated mass spectrometry has been used to identify ligands binding to proteins. It involves mixing protein and compounds, separation of protein-ligand complexes from unbound compounds, dissociation of the protein-ligand complex, separation to remove protein, and injection of the supernatant into a mass spectrometer to observe the ligand. Here we report collision-induced affinity selection mass spectrometry (CIAS-MS), which allows separation and dissociation inside the instrument. The quadrupole was used to select the ligand-protein complex and allow unbound molecules to be exhausted to vacuum. Collision-induced dissociation (CID) dissociated the protein-ligand complex, and the ion guide and resonance frequency were used to selectively detect the ligand. A known SARS-CoV-2 Nsp9 ligand, oridonin, was successfully detected when it was mixed with Nsp9. We provide proof-of-concept data that the CIAS-MS method can be used to identify binding ligands for any purified protein.
Language	English
Publishing date	2022-05-18
Publishing country	United States
Document type	Journal Article
ISSN	2694-2437
ISSN (online)	2694-2437
DOI	10.1021/acsbiomedchemau.2c00021
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Crystal structures of pertussis toxin with NAD

Sakari, Moona / Tran, Mai T / Rossjohn, Jamie / Pulliainen, Arto T / Beddoe, Travis / Littler, Dene R

The Journal of biological chemistry

2022 Volume 298, Issue 5, Page(s) 101892

Abstract: Bordetella pertussis is the causative agent of whooping cough, a highly contagious respiratory disease. Pertussis toxin (PT), a major virulence factor secreted by B. pertussis, is an AB5-type protein complex topologically related to cholera toxin. The PT ...

Abstract	Bordetella pertussis is the causative agent of whooping cough, a highly contagious respiratory disease. Pertussis toxin (PT), a major virulence factor secreted by B. pertussis, is an AB5-type protein complex topologically related to cholera toxin. The PT protein complex is internalized by host cells and follows a retrograde trafficking route to the endoplasmic reticulum, where it subsequently dissociates. The released enzymatic S1 subunit is then translocated from the endoplasmic reticulum into the cytosol and subsequently ADP-ribosylates the inhibitory alpha-subunits (Gαi) of heterotrimeric G proteins, thus promoting dysregulation of G protein-coupled receptor signaling. However, the mechanistic details of the ADP-ribosylation activity of PT are not well understood. Here, we describe crystal structures of the S1 subunit in complex with nicotinamide adenine dinucleotide (NAD+), with NAD+ hydrolysis products ADP-ribose and nicotinamide, with NAD+ analog PJ34, and with a novel NAD+ analog formed upon S1 subunit crystallization with 3-amino benzamide and NAD+, which we name benzamide amino adenine dinucleotide. These crystal structures provide unprecedented insights into pre- and post-NAD+ hydrolysis steps of the ADP-ribosyltransferase activity of PT. We propose that these data may aid in rational drug design approaches and further development of PT-specific small-molecule inhibitors.
MeSH term(s)	ADP-Ribosylation ; Adenosine Diphosphate Ribose/metabolism ; Bordetella pertussis ; Cytosol/metabolism ; NAD/metabolism ; Pertussis Toxin/chemistry ; Virulence Factors, Bordetella/chemistry
Chemical Substances	Virulence Factors, Bordetella ; NAD (0U46U6E8UK) ; Adenosine Diphosphate Ribose (20762-30-5) ; Pertussis Toxin (EC 2.4.2.31)
Language	English
Publishing date	2022-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2022.101892
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Uc I Zs.108: Show issues

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Article ; Online: Epitope-anchored contrastive transfer learning for paired CD8+ T cell receptor-antigen recognition

Zhang, Yumeng / Wang, Zhikang / Jiang, Yunzhe / Littler, Dene R / Gerstein, Mark / Purcell, Anthony W / Rossjohn, Jamie / Ou, Hong-Yu / Song, Jiangning

bioRxiv

Abstract: Understanding the mechanisms of T-cell antigen recognition that underpin adaptive immune responses is critical for the development of vaccines, immunotherapies, and treatments against autoimmune diseases. Despite extensive research efforts, the accurate ... ...

Abstract	Understanding the mechanisms of T-cell antigen recognition that underpin adaptive immune responses is critical for the development of vaccines, immunotherapies, and treatments against autoimmune diseases. Despite extensive research efforts, the accurate identification of T cell receptor (TCR)-antigen binding pairs remains a significant challenge due to the vast diversity and cross-reactivity of TCRs. Here, we propose a deep-learning framework termed Epitope-anchored Contrastive Transfer Learning (EPACT) tailored to paired human CD8<sup>+</sup> TCRs from single-cell sequencing data. Harnessing the pre-trained representations and the contrastive co-embedding space, EPACT demonstrates state-of-the-art model generalizability in predicting TCR binding specificity for unseen epitopes and distinct TCR repertoires, offering potential values for practical outcomes in real-world scenarios. The contrastive learning paradigm achieves highly precise predictions for immunodominant epitopes and facilitates interpretable analysis of epitope-specific T cells. The TCR binding strength predicted by EPACT aligns well with the surge in spike-specific immune responses targeting SARS-CoV-2 epitopes after vaccination. We further fine-tune EPACT on TCR-epitope structural data to decipher the residue-level interactions involved in T-cell antigen recognition. EPACT not only exhibits superior capabilities in quantifying inter-chain distance matrices and identifying contact residue pairs but also corroborates the presence of molecular mimicry across multiple tumor-associated antigens. Together, EPACT can serve as a useful AI approach with significant potential in practical applications and contribute toward the development of TCR-based diagnostics and immunotherapies.
Keywords	covid19
Language	English
Publishing date	2024-04-07
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2024.04.05.588255
Database	COVID19

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Article ; Online: Epitope-anchored contrastive transfer learning for paired CD8+ cell receptor-antigen recognition

Zhang, Yumeng / Wang, Zhikang / Jiang, Yunzhe / Littler, Dene R. / Gerstein, Mark / Purcell, Anthony W. / Rossjohn, Jamie / Ou, Hong-Yu / Song, Jiangning

bioRxiv

Abstract	Understanding the mechanisms of T-cell antigen recognition that underpin adaptive immune responses is critical for the development of vaccines, immunotherapies, and treatments against autoimmune diseases. Despite extensive research efforts, the accurate identification of T cell receptor (TCR)-antigen binding pairs remains a significant challenge due to the vast diversity and cross-reactivity of TCRs. Here, we propose a deep-learning framework termed Epitope-anchored Contrastive Transfer Learning (EPACT) tailored to paired human CD8<sup>+</sup> TCRs from single-cell sequencing data. Harnessing the pre-trained representations and the contrastive co-embedding space, EPACT demonstrates state-of-the-art model generalizability in predicting TCR binding specificity for unseen epitopes and distinct TCR repertoires, offering potential values for practical outcomes in real-world scenarios. The contrastive learning paradigm achieves highly precise predictions for immunodominant epitopes and facilitates interpretable analysis of epitope-specific T cells. The TCR binding strength predicted by EPACT aligns well with the surge in spike-specific immune responses targeting SARS-CoV-2 epitopes after vaccination. We further fine-tune EPACT on TCR-epitope structural data to decipher the residue-level interactions involved in T-cell antigen recognition. EPACT not only exhibits superior capabilities in quantifying inter-chain distance matrices and identifying contact residue pairs but also corroborates the presence of molecular mimicry across multiple tumor-associated antigens. Together, EPACT can serve as a useful AI approach with significant potential in practical applications and contribute toward the development of TCR-based diagnostics and immunotherapies.
Keywords	covid19
Language	English
Publishing date	2024-04-07
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2024.04.05.588255
Database	COVID19

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Article ; Online: Crystal Structure of the SARS-CoV-2 Non-structural Protein 9, Nsp9.

Littler, Dene R / Gully, Benjamin S / Colson, Rhys N / Rossjohn, Jamie

iScience

2020 Volume 23, Issue 7, Page(s) 101258

Abstract: Many of the SARS-CoV-2 proteins have related counterparts across the Severe Acute Respiratory Syndrome (SARS-CoV) family. One such protein is non-structural protein 9 (Nsp9), which is thought to mediate viral replication, overall virulence, and viral ... ...

Abstract	Many of the SARS-CoV-2 proteins have related counterparts across the Severe Acute Respiratory Syndrome (SARS-CoV) family. One such protein is non-structural protein 9 (Nsp9), which is thought to mediate viral replication, overall virulence, and viral genomic RNA reproduction. We sought to better characterize the SARS-CoV-2 Nsp9 and subsequently solved its X-ray crystal structure, in an apo form and, unexpectedly, in a peptide-bound form with a sequence originating from a rhinoviral 3C protease sequence (LEVL). The SARS-CoV-2 Nsp9 structure revealed the high level of structural conservation within the Nsp9 family. The exogenous peptide binding site is close to the dimer interface and impacted the relative juxtapositioning of the monomers within the homodimer. We have established a protocol for the production of SARS-CoV-2 Nsp9, determined its structure, and identified a peptide-binding site that warrants further study to understanding Nsp9 function.
Keywords	covid19
Language	English
Publishing date	2020-06-09
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2020.101258
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A pocket guide on how to structure SARS-CoV-2 drugs and therapies.

Littler, Dene R / MacLachlan, Bruce J / Watson, Gabrielle M / Vivian, Julian P / Gully, Benjamin S

Biochemical Society transactions

2020 Volume 48, Issue 6, Page(s) 2625–2641

Abstract: The race to identify a successful treatment for COVID19 will be defined by fundamental research into the replication cycle of the SARS-CoV-2 virus. This has identified five distinct stages from which numerous vaccination and clinical trials have emerged ... ...

Abstract	The race to identify a successful treatment for COVID19 will be defined by fundamental research into the replication cycle of the SARS-CoV-2 virus. This has identified five distinct stages from which numerous vaccination and clinical trials have emerged alongside an innumerable number of drug discovery studies currently in development for disease intervention. Informing every step of the viral replication cycle has been an unprecedented 'call-to-arms' by the global structural biology community. Of the 20 main SARS-CoV-2 proteins, 13 have been resolved structurally for SARS-CoV-2 with most having a related SARS-CoV and MERS-CoV structural homologue totalling some 300 structures currently available in public repositories. Herein, we review the contribution of structural studies to our understanding of the virus and their role in structure-based development of therapeutics.
MeSH term(s)	Antiviral Agents/chemical synthesis ; Antiviral Agents/chemistry ; Antiviral Agents/therapeutic use ; COVID-19/immunology ; COVID-19/therapy ; Drug Development/methods ; Drug Discovery/methods ; Genome, Viral ; Humans ; Models, Molecular ; Protein Structural Elements ; SARS-CoV-2/chemistry ; SARS-CoV-2/drug effects ; SARS-CoV-2/immunology ; SARS-CoV-2/physiology ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/physiology ; Structure-Activity Relationship ; Viral Structural Proteins/chemistry ; Viral Structural Proteins/physiology ; Virus Replication/drug effects ; Virus Replication/physiology ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents ; Spike Glycoprotein, Coronavirus ; Viral Structural Proteins ; spike protein, SARS-CoV-2
Language	English
Publishing date	2020-11-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20200396
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 944: Show issues

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Article ; Online: Complimentary electrostatics dominate T-cell receptor binding to a psoriasis-associated peptide antigen presented by human leukocyte antigen C∗06:02.

Anand, Sushma / Littler, Dene R / Mobbs, Jesse I / Braun, Asolina / Baker, Daniel G / Tennant, Luke / Purcell, Anthony W / Vivian, Julian P / Rossjohn, Jamie

The Journal of biological chemistry

2023 Volume 299, Issue 7, Page(s) 104930

Abstract: Psoriasis is a chronic skin disease characterized by hyperproliferative epidermal lesions infiltrated by autoreactive T cells. Individuals expressing the human leukocyte antigen (HLA) C∗06:02 allele are at highest risk for developing psoriasis. An ... ...

Abstract	Psoriasis is a chronic skin disease characterized by hyperproliferative epidermal lesions infiltrated by autoreactive T cells. Individuals expressing the human leukocyte antigen (HLA) C∗06:02 allele are at highest risk for developing psoriasis. An autoreactive T cell clone (termed Vα3S1/Vβ13S1) isolated from psoriatic plaques is selective for HLA-C∗06:02, presenting a peptide derived from the melanocyte-specific autoantigen ADAMTSL5 (VRSRRCLRL). Here we determine the crystal structure of this psoriatic TCR-HLA-C∗06:02 ADAMTSL5 complex with a stabilized peptide. Docking of the TCR involves an extensive complementary charge network formed between negatively charged TCR residues interleaving with exposed arginine residues from the self-peptide and the HLA-C∗06:02 α1 helix. We probed these interactions through mutagenesis and activation assays. The charged interface spans the polymorphic region of the C1/C2 HLA group. Notably the peptide-binding groove of HLA-C∗06:02 appears exquisitely suited for presenting highly charged Arg-rich epitopes recognized by this acidic psoriatic TCR. Overall, we provide a structural basis for understanding the engagement of melanocyte antigen-presenting cells by a TCR implicated in psoriasis while simultaneously expanding our knowledge of how TCRs engage HLA-C.
MeSH term(s)	Humans ; HLA-C Antigens ; Static Electricity ; Peptides/chemistry ; Psoriasis/pathology ; Receptors, Antigen, T-Cell/genetics ; ADAMTS Proteins
Chemical Substances	HLA-C Antigens ; Peptides ; Receptors, Antigen, T-Cell ; ADAMTSL5 protein, human (EC 3.4.24.-) ; ADAMTS Proteins (EC 3.4.24.-)
Language	English
Publishing date	2023-06-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.104930
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Uc I Zs.108: Show issues

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