Virtual Screening of Phytochemicals to Novel Target (HAT) Rtt109 in Pneumocystis Jirovecii using Bioinformatics Tools

Sugumar, Ramya; Adithavarman, Abhinand Ponneri; Dakshinamoorthi, Anusha; David, Darling Chellathai; Ragunath, P K

doi:10.7860/jcdr/2016/16029.7374

Cited by 2 publications

(2 citation statements)

References 23 publications

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“…Several groups have tried to screen inhibitors based on Rtt109 but failed. 36,37 Considering that PcVps75 can activate Rtt109 catalytic acetylating H3K9 and H3K27 and function in the DNA damage response by mediating the interaction with histones rather than forming a complex with Rtt109, new choices in drug design may be available based on the Rtt109-dependent histone acetylation pathway.…”

Section: Discussionmentioning

confidence: 99%

Structural basis for the acetylation of histone H3K9 and H3K27 mediated by the histone chaperone Vps75 in Pneumocystis carinii

Zhang

Yang

Dou

et al. 2019

Sig Transduct Target Ther

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Rtt109 is a histone acetyltransferase (HAT) that is a potential therapeutic target in conditioned pathogenic fungi Pneumocystis carinii (P. carinii) . The histone chaperone Vps75 can stimulate the Rtt109-dependent acetylation of several histone H3 lysines and preferentially acetylates H3K9 and H3K27 within canonical histone (H3–H4) 2 tetramers. Vps75 shows two protein conformations assembled into dimeric and tetrameric forms, but the roles played by multimeric forms of Vps75 in Rtt109-mediated histone acetylation remain elusive. In P. carinii , we identified that Vps75 (PcVps75) dimers regulate H3K9 and H3K27 acetylation by directly interacting with histone (H3–H4) 2 tetramers, rather than by forming a Vps75-Rtt109 complex. For PcVps75 tetramers, the major histone-binding surface is buried within a walnut-like structure in the absence of a histone cargo. Based on crystal structures of dimeric and tetrameric forms of PcVps75, as well as HAT assay data, we confirmed that residues 192E, 193D, 194E, 195E, and 196E and the disordered C-terminal tail (residues 224–250) of PcVps75 mediate interactions with histones and are important for the Rtt109 in P. carinii (PcRtt109)-mediated acetylation of H3K9 and H3K27, both in vitro and in yeast cells. Furthermore, expressing PcRtt109 alone or in combination with PcVps75 variants that cannot effectively bind histones could not fully restore cellular growth in the presence of genotoxic agents that block DNA replication owing to the absence of H3K9 and H3K27 acetylation. Together, these data indicate that the interaction between PcVps75 and histone (H3–H4) 2 tetramers is a critical regulator of the Rtt109-mediated acetylation of H3K9 and H3K27.

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Section: Discussionmentioning

confidence: 99%

Structural basis for the acetylation of histone H3K9 and H3K27 mediated by the histone chaperone Vps75 in Pneumocystis carinii

Zhang

Yang

Dou

et al. 2019

Sig Transduct Target Ther

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“…More specific targeting for identifying some leads in antimicrobials was undertaken for histone acetyltransferase Rtt109, a potential therapeutic target in Pneumocystis jirovecii species (Sugumar et al, 2016). Bioinformatics was used to find phytochemicals which could bind with the above targets.…”

Section: Discoverymentioning

confidence: 99%

Clinical Pharmacology in India-A Systematic Review of Research in the Past 5 Years

Shafiq

Kakkar²,

Malhotra³

2018

Proceedings of the Indian National Science Academy

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The Indian National Science Academy has published two Status Reports on Pharmacological Research (1984 & 2000). The International Council for Science (ICSU) National Committee for Pharmacology has commissioned the third status report on Pharmacological Research in India covering the last 5 years. This report covers research done in chemotherapy of infectious diseases barring tropical diseases. The areas covered in chemotherapy included drug-discovery, observational studies, pharmacokinetics-pharmacodynamics and safety studies. We largely relied on Pubmed for our search. Work conducted in India and where at least one of the authors was affiliated to the Department of Pharmacology was included. Salient features of the studies were summarized. Lacunae in the current scene of research were explored and way forward suggested.

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Virtual Screening of Phytochemicals to Novel Target (HAT) Rtt109 in Pneumocystis Jirovecii using Bioinformatics Tools

Cited by 2 publications

References 23 publications

Structural basis for the acetylation of histone H3K9 and H3K27 mediated by the histone chaperone Vps75 in Pneumocystis carinii

Structural basis for the acetylation of histone H3K9 and H3K27 mediated by the histone chaperone Vps75 in Pneumocystis carinii

Clinical Pharmacology in India-A Systematic Review of Research in the Past 5 Years

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