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  1. Article ; Online: IgG1 and IgG4 antibodies sample initial structure dependent local conformational states and exhibit non-identical Fab dynamics.

    Natesan, Ramakrishnan / Agrawal, Neeraj J

    Scientific reports

    2023  Volume 13, Issue 1, Page(s) 4791

    Abstract: We have investigated the dynamics of two [Formula: see text]-immunoglobulin molecules, IgG1 and IgG4, using long all atom molecular dynamics simulations. We first show that the de novo structures of IgG1 and IgG4 predicted using AlphaFold, with no ... ...

    Abstract We have investigated the dynamics of two [Formula: see text]-immunoglobulin molecules, IgG1 and IgG4, using long all atom molecular dynamics simulations. We first show that the de novo structures of IgG1 and IgG4 predicted using AlphaFold, with no interactions between the fragment crystallizable (Fc) domain and the antigen fragment binding domain (Fab), eventually relaxes to a state with persistent Fc-Fab interactions that mirrors experimentally resolved structures. We quantified the conformational space sampled by antibody trajectories spawned from six different initial structures and show that the individual trajectories only sample states bound by a local minimum and display very little mixing in their conformational states. Furthermore, the dynamics of the individual Fab domains are strongly dependent on the initial crystal structure and isotype. In all conditions, we observe non-identical dynamics between the Fab arms in an antibody. For a six-bead coarse grained model, we show that non-covalent Fc-Fab interactions can modulate the stiffnesses associated with Fc-Fab distances, angles, and dihedral angles by up to three orders of magnitude. Our results clearly illustrate the inherent complexities in studying antibody dynamics and highlight the need to include non-identical Fab dynamics as an inherent feature in computational models of therapeutic antibodies.
    MeSH term(s) Immunoglobulin G ; Immunoglobulin Fab Fragments/chemistry ; Molecular Conformation ; Immunoglobulin Fc Fragments/metabolism
    Chemical Substances Immunoglobulin G ; Immunoglobulin Fab Fragments ; Immunoglobulin Fc Fragments
    Language English
    Publishing date 2023-03-23
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-023-32067-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Non-covalent Fc-Fab interactions significantly alter internal dynamics of an IgG1 antibody.

    Natesan, Ramakrishnan / Agrawal, Neeraj J

    Scientific reports

    2022  Volume 12, Issue 1, Page(s) 9321

    Abstract: The fragment-antigen-binding arms (Fab1 and Fab2) in a canonical immunoglobulin G (IgG) molecule have identical sequences and hence are always expected to exhibit symmetric conformations and dynamics. Using long all atom molecular simulations of a human ... ...

    Abstract The fragment-antigen-binding arms (Fab1 and Fab2) in a canonical immunoglobulin G (IgG) molecule have identical sequences and hence are always expected to exhibit symmetric conformations and dynamics. Using long all atom molecular simulations of a human IgG1 crystal structure 1HZH, we demonstrate that the translational and rotational dynamics of Fab1 and Fab2 also strongly depend on their interactions with each other and with the fragment-crystallizable (Fc) region. We show that the Fab2 arm in the 1HZH structure is non-covalently bound to the Fc region via long-lived hydrogen bonds, involving its light chain and both heavy chains of the Fc region. These highly stable interactions stabilize non-trivial conformer states with constrained fluctuations. We observe subtle modifications in Fab1 dynamics in response to Fab2-Fc interactions that points to novel allosteric interactions between the Fab arms. These results yield novel insights into the inter- and intra-fragment motions of immunoglobulins which could help us better understand the relation between their structure and function.
    MeSH term(s) Humans ; Immunoglobulin Fab Fragments/chemistry ; Immunoglobulin Fc Fragments/chemistry ; Immunoglobulin G
    Chemical Substances Immunoglobulin Fab Fragments ; Immunoglobulin Fc Fragments ; Immunoglobulin G
    Language English
    Publishing date 2022-06-04
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-022-13370-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Heterogeneity in Disulfide Bond Reduction in IgG1 Antibodies Is Governed by Solvent Accessibility of the Cysteines.

    Natesan, Ramakrishnan / Dykstra, Andrew B / Banerjee, Akash / Agrawal, Neeraj J

    Antibodies (Basel, Switzerland)

    2023  Volume 12, Issue 4

    Abstract: We studied unpaired cysteine levels and disulfide bond susceptibility in four different γ-immunoglobulin antibodies using liquid chromatography-mass spectrometry. Our choice of differential alkylating agents ensures that the differential peaks are non- ... ...

    Abstract We studied unpaired cysteine levels and disulfide bond susceptibility in four different γ-immunoglobulin antibodies using liquid chromatography-mass spectrometry. Our choice of differential alkylating agents ensures that the differential peaks are non-overlapping, thus allowing us to accurately quantify free cysteine levels. For each cysteine residue, we observed no more than 5% to be unpaired, and the free cysteine levels across antibodies were slightly higher in those containing lambda light chains. Interchain and hinge residues were highly susceptible to reducing stresses and showed a 100-1000-fold higher rate of reduction compared to intrachain cysteines. Estimations of the solvent-accessible surface for individual cysteines in IgG1, using an implicit all-atom molecular dynamics simulation, show that interchain and hinge cysteines have >1000-fold higher solvent accessibility compared to intrachain cysteines. Further analyses show that solvent accessibility and the rate of reduction are linearly correlated. Our work clearly establishes the fact that a cysteine's accessibility to the surrounding solvent is one of the primary determinants of its disulfide bond stability.
    Language English
    Publishing date 2023-12-13
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2661514-9
    ISSN 2073-4468 ; 2073-4468
    ISSN (online) 2073-4468
    ISSN 2073-4468
    DOI 10.3390/antib12040083
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Toppling the HAT to Treat Lethal Prostate Cancer.

    Rasool, Reyaz Ur / Natesan, Ramakrishnan / Asangani, Irfan A

    Cancer discovery

    2021  Volume 11, Issue 5, Page(s) 1011–1013

    Abstract: In this issue ... ...

    Abstract In this issue of
    MeSH term(s) Androgen Antagonists ; Cell Line, Tumor ; Genes, myc ; Humans ; Male ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/genetics ; Receptors, Androgen/genetics
    Chemical Substances Androgen Antagonists ; Receptors, Androgen
    Language English
    Publishing date 2021-05-04
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 2625242-9
    ISSN 2159-8290 ; 2159-8274
    ISSN (online) 2159-8290
    ISSN 2159-8274
    DOI 10.1158/2159-8290.CD-21-0184
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Active Remodeling of Chromatin and Implications for In Vivo Folding

    Natesan, Ramakrishnan / Gowrishankar, Kripa / Kuttippurathu, Lakshmi / Kumar, P. B. Sunil / Rao, Madan

    Journal of physical chemistry. 2021 Dec. 24, v. 126, no. 1

    2021  

    Abstract: Building on the observation that chromatin compaction can be locally modulated by activity, we propose a model of in vivo chromatin as an active polymer and study its large scale conformations. In particular, we study an active mechanochemical model of ... ...

    Abstract Building on the observation that chromatin compaction can be locally modulated by activity, we propose a model of in vivo chromatin as an active polymer and study its large scale conformations. In particular, we study an active mechanochemical model of chromosomal folding based on the interplay among polymer elasticity, confinement, topological constraints, and fluctuating active stresses arising from the ATP-dependent action of a variety of chromatin-associated protein machines and chromatin-remodeling proteins and their stochastic turnover. We find that activity drives the chromatin to a nonequilibrium steady state; the statistics of conformations in this nonequilibrium steady state are consistent with recent measurements on intrachromosomal contact probabilities and chromosomal compaction. The contact exponents at steady state show a systematic variation with changes in the nature of activity and the rates of turnover. The steady state configuration of the active chromatin in two dimensions resembles a space-filling Peano curve, which might have implications for the optimization of genome information storage.
    Keywords chromatin ; genome ; information storage ; mechanochemistry ; models ; physical chemistry ; polymers ; statistics ; topology
    Language English
    Dates of publication 2021-1224
    Size p. 100-109.
    Publishing place American Chemical Society
    Document type Article
    ISSN 1520-5207
    DOI 10.1021/acs.jpcb.1c08655
    Database NAL-Catalogue (AGRICOLA)

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  6. Article: Epigenetic Regulation of Chromatin in Prostate Cancer.

    Natesan, Ramakrishnan / Aras, Shweta / Effron, Samuel Sander / Asangani, Irfan A

    Advances in experimental medicine and biology

    2020  Volume 1210, Page(s) 379–407

    Abstract: Epigenetics refers to mitotically/meiotically heritable mechanisms that regulate gene transcription without a need for changes in the DNA code. Covalent modifications of DNA, in the form of methylation, and histone post-translational modifications, in ... ...

    Abstract Epigenetics refers to mitotically/meiotically heritable mechanisms that regulate gene transcription without a need for changes in the DNA code. Covalent modifications of DNA, in the form of methylation, and histone post-translational modifications, in the form of acetylation and methylation, constitute the epigenetic code of a cell. Both DNA and histone modifications are highly dynamic and often work in unison to define the epigenetic state of a cell. Most epigenetic mechanisms regulate gene transcription by affecting localized/genome-wide transitions between heterochromatin and euchromatin states, thereby altering the accessibility of the transcriptional machinery and in turn, reduce/increase transcriptional output. Altered chromatin structure is associated with cancer progression, and epigenetic plasticity primarily governs the resistance of cancer cells to therapeutic agents. In this chapter, we specifically focus on regulators of histone methylation and acetylation, the two well-studied chromatin post-translational modifications, in the context of prostate cancer.
    MeSH term(s) Acetylation ; Chromatin/genetics ; DNA Methylation ; Epigenesis, Genetic ; Histones/chemistry ; Histones/metabolism ; Humans ; Male ; Prostatic Neoplasms/genetics ; Protein Processing, Post-Translational
    Chemical Substances Chromatin ; Histones
    Language English
    Publishing date 2020-01-03
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2214-8019 ; 0065-2598
    ISSN (online) 2214-8019
    ISSN 0065-2598
    DOI 10.1007/978-3-030-32656-2_17
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19.

    Deng, Qu / Rasool, Reyaz Ur / Russell, Ronnie M / Natesan, Ramakrishnan / Asangani, Irfan A

    iScience

    2021  Volume 24, Issue 3, Page(s) 102254

    Abstract: Epidemiological data showing increased severity and mortality of COVID-19 in men suggests a potential role for androgen in SARS-CoV-2 infection. Here, we present evidence for the transcriptional regulation of SARS-CoV-2 host cell receptor ACE2 and ... ...

    Abstract Epidemiological data showing increased severity and mortality of COVID-19 in men suggests a potential role for androgen in SARS-CoV-2 infection. Here, we present evidence for the transcriptional regulation of SARS-CoV-2 host cell receptor ACE2 and TMPRSS2 by androgen in mouse and human cells. Additionally, we demonstrate the endogenous interaction between TMPRSS2 and ACE2 in human cells and validate ACE2 as a TMPRSS2 substrate. Furthermore, camostat-a TMPRSS2 inhibitor-blocked the cleavage of pseudotype SARS-CoV-2 surface Spike without disrupting TMPRSS2-ACE2 interaction, thus providing evidence for the first time of a direct role of TMPRSS2 in priming the SARS-CoV-2 Spike, required for viral fusion to the host cell. Importantly, androgen-deprivation, anti-androgens, or camostat attenuated the SARS-CoV-2 S-mediated cellular entry. Together, our data provide a strong rationale for clinical evaluations of TMPRSS2 inhibitors and androgen-deprivation therapy/androgen receptor antagonists alone or in combination with antiviral drugs as early as clinically possible to prevent COVID-19 progression.
    Language English
    Publishing date 2021-03-01
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2021.102254
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Active Remodeling of Chromatin and Implications for

    Natesan, Ramakrishnan / Gowrishankar, Kripa / Kuttippurathu, Lakshmi / Kumar, P B Sunil / Rao, Madan

    The journal of physical chemistry. B

    2021  Volume 126, Issue 1, Page(s) 100–109

    Abstract: Building on the observation that chromatin compaction can be locally modulated by activity, we propose a model ... ...

    Abstract Building on the observation that chromatin compaction can be locally modulated by activity, we propose a model of
    MeSH term(s) Chromatin ; Chromosomes ; Genome ; Molecular Conformation ; Polymers
    Chemical Substances Chromatin ; Polymers
    Language English
    Publishing date 2021-12-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1520-5207
    ISSN (online) 1520-5207
    DOI 10.1021/acs.jpcb.1c08655
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling.

    Walter, David M / Gladstein, Amy C / Doerig, Katherine R / Natesan, Ramakrishnan / Baskaran, Saravana G / Gudiel, A Andrea / Adler, Keren M / Acosta, Jonuelle O / Wallace, Douglas C / Asangani, Irfan A / Feldser, David M

    Communications biology

    2023  Volume 6, Issue 1, Page(s) 255

    Abstract: SETD2 is a tumor suppressor that is frequently inactivated in several cancer types. The mechanisms through which SETD2 inactivation promotes cancer are unclear, and whether targetable vulnerabilities exist in these tumors is unknown. Here we identify ... ...

    Abstract SETD2 is a tumor suppressor that is frequently inactivated in several cancer types. The mechanisms through which SETD2 inactivation promotes cancer are unclear, and whether targetable vulnerabilities exist in these tumors is unknown. Here we identify heightened mTORC1-associated gene expression programs and functionally higher levels of oxidative metabolism and protein synthesis as prominent consequences of Setd2 inactivation in KRAS-driven mouse models of lung adenocarcinoma. Blocking oxidative respiration and mTORC1 signaling abrogates the high rates of tumor cell proliferation and tumor growth specifically in SETD2-deficient tumors. Our data nominate SETD2 deficiency as a functional marker of sensitivity to clinically actionable therapeutics targeting oxidative respiration and mTORC1 signaling.
    MeSH term(s) Animals ; Mice ; Adenocarcinoma of Lung/genetics ; Genes, Tumor Suppressor ; Lung Neoplasms/genetics ; Mechanistic Target of Rapamycin Complex 1/genetics ; Oxidative Stress ; Histone-Lysine N-Methyltransferase/genetics
    Chemical Substances Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; SETD2 protein, mouse (EC 2.1.1.43) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43)
    Language English
    Publishing date 2023-03-10
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-023-04618-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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