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  1. Article ; Online: Structural basis for the inhibition mechanism of the DNA polymerase holoenzyme from mpox virus.

    Shen, Yaping / Li, Yaning / Yan, Renhong

    Structure (London, England : 1993)

    2024  

    Abstract: There are three key components at the core of the mpox virus (MPXV) DNA polymerase holoenzyme: DNA polymerase F8, processivity factors A22, and the Uracil-DNA glycosylase E4. The holoenzyme is recognized as a vital antiviral target because MPXV ... ...

    Abstract There are three key components at the core of the mpox virus (MPXV) DNA polymerase holoenzyme: DNA polymerase F8, processivity factors A22, and the Uracil-DNA glycosylase E4. The holoenzyme is recognized as a vital antiviral target because MPXV replicates in the cytoplasm of host cells. Nucleotide analogs such as cidofovir and cytarabine (Ara-C) have shown potential in curbing MPXV replication and they also display promise against other poxviruses. However, the mechanism behind their inhibitory effects remains unclear. Here, we present the cryo-EM structure of the DNA polymerase holoenzyme F8/A22/E4 bound with its competitive inhibitor Ara-C-derived cytarabine triphosphate (Ara-CTP) at an overall resolution of 3.0 Å and reveal its inhibition mechanism. Ara-CTP functions as a direct chain terminator in proximity to the deoxycytidine triphosphate (dCTP)-binding site. The extra hydrogen bond formed with Asn665 makes it more potent in binding than dCTP. Asn665 is conserved among eukaryotic B-family polymerases.
    Language English
    Publishing date 2024-03-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1213087-4
    ISSN 1878-4186 ; 0969-2126
    ISSN (online) 1878-4186
    ISSN 0969-2126
    DOI 10.1016/j.str.2024.03.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4141: Show issues Location:
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  2. Article ; Online: Structural insight into the assembly and working mechanism of helicase-primase D5 from Mpox virus.

    Li, Yaning / Zhu, Jing / Guo, Yingying / Yan, Renhong

    Nature structural & molecular biology

    2024  Volume 31, Issue 1, Page(s) 68–81

    Abstract: The Mpox pandemic, caused by the Mpox virus (or monkeypox virus, MPXV), has gained global attention. The D5 protein, a putative helicase-primase found in MPXV, plays a vital role in viral replication and genome uncoating. Here we determined multiple cryo- ...

    Abstract The Mpox pandemic, caused by the Mpox virus (or monkeypox virus, MPXV), has gained global attention. The D5 protein, a putative helicase-primase found in MPXV, plays a vital role in viral replication and genome uncoating. Here we determined multiple cryo-EM structures of full-length hexameric D5 in diverse states. These states were captured during ATP hydrolysis while moving along the single-stranded DNA (ssDNA) track. Through comprehensive structural analysis combined with the helicase activity system, we revealed that when the primase domain is truncated or the interaction between the primase and helicase domains is disrupted, the double-stranded DNA (dsDNA) unwinds into ssDNA, suggesting a critical regulatory role of the primase domain. Two transition states bound with ssDNA substrate during unwinding reveals that two ATP molecules were consumed to drive DNA moving forward two nucleotides. Collectively, our findings shed light on the molecular mechanism that links ATP hydrolysis to the DNA unwinding in poxviruses.
    MeSH term(s) DNA Primase/chemistry ; DNA Primase/genetics ; DNA Primase/metabolism ; Monkeypox virus/genetics ; Monkeypox virus/metabolism ; DNA Helicases/metabolism ; DNA/chemistry ; DNA, Single-Stranded ; Adenosine Triphosphate/metabolism
    Chemical Substances DNA Primase (EC 2.7.7.-) ; DNA Helicases (EC 3.6.4.-) ; DNA (9007-49-2) ; DNA, Single-Stranded ; Adenosine Triphosphate (8L70Q75FXE)
    Language English
    Publishing date 2024-01-04
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2126708-X
    ISSN 1545-9985 ; 1545-9993
    ISSN (online) 1545-9985
    ISSN 1545-9993
    DOI 10.1038/s41594-023-01142-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MG 56: Show issues

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  3. Article: Biological characteristics of γδT cells and application in tumor immunotherapy.

    Zhu, Renhong / Yan, Qian / Wang, Yashu / Wang, Keqiang

    Frontiers in genetics

    2023  Volume 13, Page(s) 1077419

    Abstract: Human γδT cells are a special immune cell type which exist in small quantities in the body, do not require processing and presentation for antigen recognition, and have non-major histocompatibility complex (MHC)-restricted immune response. They play an ... ...

    Abstract Human γδT cells are a special immune cell type which exist in small quantities in the body, do not require processing and presentation for antigen recognition, and have non-major histocompatibility complex (MHC)-restricted immune response. They play an important role in the body's anti-tumor, anti-infection, immune regulation, immune surveillance and maintenance of immune tolerance. This article reviews the generation and development of human γδT cells, genetic characteristics, classification, recognition and role of antigens, and research progress in tumor immunotherapy.
    Language English
    Publishing date 2023-01-04
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2606823-0
    ISSN 1664-8021
    ISSN 1664-8021
    DOI 10.3389/fgene.2022.1077419
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Structural basis for the assembly of the DNA polymerase holoenzyme from a monkeypox virus variant.

    Li, Yaning / Shen, Yaping / Hu, Ziwei / Yan, Renhong

    Science advances

    2023  Volume 9, Issue 16, Page(s) eadg2331

    Abstract: The ongoing global pandemic caused by a variant of the monkeypox (or mpox) virus (MPXV) has prompted widespread concern. The MPXV DNA polymerase holoenzyme, consisting of F8, A22, and E4, is vital for replicating the viral genome and represents a crucial ...

    Abstract The ongoing global pandemic caused by a variant of the monkeypox (or mpox) virus (MPXV) has prompted widespread concern. The MPXV DNA polymerase holoenzyme, consisting of F8, A22, and E4, is vital for replicating the viral genome and represents a crucial target for the development of antiviral drugs. However, the assembly and working mechanism for the DNA polymerase holoenzyme of MPXV remains elusive. Here, we present the cryo-electron microscopy (cryo-EM) structure of the DNA polymerase holoenzyme at an overall resolution of 3.5 Å. Unexpectedly, the holoenzyme is assembled as a dimer of heterotrimers, of which the extra interface between the thumb domain of F8 and A22 shows a clash between A22 and substrate DNA, suggesting an autoinhibition state. Addition of exogenous double-stranded DNA shifts the hexamer into trimer exposing DNA binding sites, potentially representing a more active state. Our findings provide crucial steps toward developing targeted antiviral therapies for MPXV and related viruses.
    MeSH term(s) Humans ; Monkeypox virus/genetics ; Cryoelectron Microscopy ; Mpox (monkeypox) ; DNA-Directed DNA Polymerase
    Chemical Substances DNA-Directed DNA Polymerase (EC 2.7.7.7)
    Language English
    Publishing date 2023-04-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.adg2331
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  5. Article: Structures of ACE2-SIT1 recognized by Omicron variants of SARS-CoV-2.

    Shen, Yaping / Wang, Jianhui / Li, Yaning / Zhang, Yuanyuan / Tian, Ruilin / Yan, Renhong

    Cell discovery

    2022  Volume 8, Issue 1, Page(s) 123

    Language English
    Publishing date 2022-11-16
    Publishing country England
    Document type Letter
    ISSN 2056-5968
    ISSN 2056-5968
    DOI 10.1038/s41421-022-00488-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Structural Basis for the Enhanced Infectivity and Immune Evasion of Omicron Subvariants.

    Li, Yaning / Shen, Yaping / Zhang, Yuanyuan / Yan, Renhong

    Viruses

    2023  Volume 15, Issue 6

    Abstract: The Omicron variants of SARS-CoV-2 have emerged as the dominant strains worldwide, causing the COVID-19 pandemic. Each Omicron subvariant contains at least 30 mutations on the spike protein (S protein) compared to the original wild-type (WT) strain. Here ...

    Abstract The Omicron variants of SARS-CoV-2 have emerged as the dominant strains worldwide, causing the COVID-19 pandemic. Each Omicron subvariant contains at least 30 mutations on the spike protein (S protein) compared to the original wild-type (WT) strain. Here we report the cryo-EM structures of the trimeric S proteins from the BA.1, BA.2, BA.3, and BA.4/BA.5 subvariants, with BA.4 and BA.5 sharing the same S protein mutations, each in complex with the surface receptor ACE2. All three receptor-binding domains of the S protein from BA.2 and BA.4/BA.5 are "up", while the BA.1 S protein has two "up" and one "down". The BA.3 S protein displays increased heterogeneity, with the majority in the all "up" RBD state. The different conformations preferences of the S protein are consistent with their varied transmissibility. By analyzing the position of the glycan modification on Asn343, which is located at the S309 epitopes, we have uncovered the underlying immune evasion mechanism of the Omicron subvariants. Our findings provide a molecular basis of high infectivity and immune evasion of Omicron subvariants, thereby offering insights into potential therapeutic interventions against SARS-CoV-2 variants.
    MeSH term(s) Humans ; COVID-19 ; Immune Evasion ; Pandemics ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus/genetics
    Chemical Substances Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
    Language English
    Publishing date 2023-06-20
    Publishing country Switzerland
    Document type Journal Article ; 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/v15061398
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Structural insight into the substrate recognition and transport mechanism of amino acid transporter complex ACE2-B

    Li, Yaning / Chen, Yiming / Zhang, Yuanyuan / Shen, Yaping / Xu, Kangtai / Liu, Yaqi / Wang, Zilong / Yan, Renhong

    Cell discovery

    2023  Volume 9, Issue 1, Page(s) 93

    Language English
    Publishing date 2023-09-08
    Publishing country England
    Document type Letter
    ISSN 2056-5968
    ISSN 2056-5968
    DOI 10.1038/s41421-023-00596-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Cryo-EM structures of SARS-CoV-2 BA.2-derived subvariants spike in complex with ACE2 receptor.

    Li, Yaning / Ren, Chang / Shen, Yaping / Zhang, Yuanyuan / Chen, Jin / Zheng, Jiangnan / Tian, Ruijun / Cao, Liwei / Yan, Renhong

    Cell discovery

    2023  Volume 9, Issue 1, Page(s) 108

    Language English
    Publishing date 2023-11-02
    Publishing country England
    Document type Letter
    ISSN 2056-5968
    ISSN 2056-5968
    DOI 10.1038/s41421-023-00607-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Cryo-EM structure of the human Asc-1 transporter complex.

    Li, Yaning / Guo, Yingying / Bröer, Angelika / Dai, Lu / Brӧer, Stefan / Yan, Renhong

    Nature communications

    2024  Volume 15, Issue 1, Page(s) 3036

    Abstract: The Alanine-Serine-Cysteine transporter 1 (Asc-1 or SLC7A10) forms a crucial heterodimeric transporter complex with 4F2hc (SLC3A2) through a covalent disulfide bridge. This complex enables the sodium-independent transport of small neutral amino acids, ... ...

    Abstract The Alanine-Serine-Cysteine transporter 1 (Asc-1 or SLC7A10) forms a crucial heterodimeric transporter complex with 4F2hc (SLC3A2) through a covalent disulfide bridge. This complex enables the sodium-independent transport of small neutral amino acids, including L-Alanine (L-Ala), Glycine (Gly), and D-Serine (D-Ser), within the central nervous system (CNS). D-Ser and Gly are two key endogenous glutamate co-agonists that activate N-methyl-d-aspartate (NMDA) receptors by binding to the allosteric site. Mice deficient in Asc-1 display severe symptoms such as tremors, ataxia, and seizures, leading to early postnatal death. Despite its physiological importance, the functional mechanism of the Asc-1-4F2hc complex has remained elusive. Here, we present cryo-electron microscopy (cryo-EM) structures of the human Asc-1-4F2hc complex in its apo state, D-Ser bound state, and L-Ala bound state, resolved at 3.6 Å, 3.5 Å, and 3.4 Å, respectively. Through detailed structural analysis and transport assays, we uncover a comprehensive alternating access mechanism that underlies conformational changes in the complex. In summary, our findings reveal the architecture of the Asc-1 and 4F2hc complex and provide valuable insights into substrate recognition and the functional cycle of this essential transporter complex.
    MeSH term(s) Mice ; Humans ; Animals ; Cryoelectron Microscopy ; Serine/metabolism ; Membrane Transport Proteins/genetics ; Glycine ; Cysteine
    Chemical Substances Serine (452VLY9402) ; Membrane Transport Proteins ; Glycine (TE7660XO1C) ; Cysteine (K848JZ4886)
    Language English
    Publishing date 2024-04-08
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-024-47468-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: ACE2, B

    Zhang, Yuanyuan / Yan, Renhong / Zhou, Qiang

    Current opinion in structural biology

    2022  Volume 74, Page(s) 102388

    Abstract: The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a public health crisis and led to tremendous economic devastation. The spike protein (S) of SARS-CoV-2 hijacks ... ...

    Abstract The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a public health crisis and led to tremendous economic devastation. The spike protein (S) of SARS-CoV-2 hijacks the angiotensin converting enzyme 2 (ACE2) as a receptor for virus entry, representing the initial step of viral infection. S is one of the major targets for development of the antiviral drugs, antibodies, and vaccines. ACE2 is a peptidase that plays a physiologically important role in the renin-angiotensin system. Concurrently, it also forms dimer of heterodimer with the neutral amino acid transporter B
    MeSH term(s) Angiotensin-Converting Enzyme 2 ; COVID-19 ; Humans ; Peptidyl-Dipeptidase A/chemistry ; Peptidyl-Dipeptidase A/metabolism ; Protein Binding ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/metabolism
    Chemical Substances Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
    Language English
    Publishing date 2022-04-20
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 1068353-7
    ISSN 1879-033X ; 0959-440X
    ISSN (online) 1879-033X
    ISSN 0959-440X
    DOI 10.1016/j.sbi.2022.102388
    Database MEDical Literature Analysis and Retrieval System OnLINE

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