Small Conformational Changes Underlie Evolution of Resistance to NNRTI in HIV Reverse Transcriptase

Srivastava, Ashutosh; Birari, Varun; Sinha, Somdatta

doi:10.1016/j.bpj.2020.04.008

Cited by 5 publications

(3 citation statements)

References 53 publications

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“…Protein contact network (PCN) and Molecular dynamic simulation (MDS) have been very useful approaches for analyzing nominal conformational changes crucial for large conformational effects on the function and inhibitor binding of proteins. 22 These methods have already been used in various studies such as understanding the dynamics of mutant proteins, 23 , 24 structural flexibility 25 structure‐function relationship 26 identifying crucial functional residues in proteins. 27 Recently, the PCN approach has also been applied to study a structural comparison of SARS‐CoV‐1 and SARS‐CoV‐2 M pro in apo and inhibitor bound states.…”

Section: Introductionmentioning

confidence: 99%

Probing structural basis for enhanced binding of SARS‐CoV‐2 P.1 variant spike protein with the human ACE2 receptor

Lata

Akif

2022

J of Cellular Biochemistry

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The initial step of infection by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) involves the binding of receptor binding domain (RBD) of the spike protein to the angiotensin converting enzyme 2 (ACE2) receptor. Each successive wave of SARS‐CoV‐2 reports emergence of many new variants, which is associated with mutations in the RBD as well as other parts of the spike protein. These mutations are reported to have enhanced affinity towards the ACE2 receptor as well as are also crucial for the virus transmission. Many computational and experimental studies have demonstrated the effect of individual mutation on the RBD‐ACE2 binding. However, the cumulative effect of mutations on the RBD and away from the RBD was not investigated in detail. We report here a comparative analysis on the structural communication and dynamics of the RBD and truncated S1 domain of spike protein in complex with the ACE2 receptor from SARS‐CoV‐2 wild type and its P.1 variant. Our integrative network and dynamics approaches highlighted a subtle conformational changes in the RBD as well as truncated S1 domain of spike protein at the protein contact level, responsible for the increased affinity with the ACE2 receptor. Moreover, our study also identified the commonalities and differences in the dynamics of the interactions between spike protein of SARS‐CoV‐2 wild type and its P.1 variant with the ACE2 receptor. Further, our investigation yielded an understanding towards identification of the unique RBD residues crucial for the interaction with the ACE2 host receptor. Overall, the study provides an insight for designing better therapeutics against the circulating P.1 variants as well as other future variants.

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Section: Introductionmentioning

confidence: 99%

Probing structural basis for enhanced binding of SARS‐CoV‐2 P.1 variant spike protein with the human ACE2 receptor

Lata

Akif

2022

J of Cellular Biochemistry

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“…To understand the role of changes in edge frequency on the local and global architecture of ID peptide and REV-ERBβ LBD, we performed community structure analysis on PCNs obtained above. Community structure analysis has been used widely to understand the protein architecture and its direct relevance on functionality [30][31][32] .The communities in a protein contact network are represented by the group of highly connected nodes within a region than other regions of a protein. We performed community structure detection using Louvain algorithm 33 for the four networks and compared them for Apo-6WMQ-Aagonist/antagonist and Apo-6WMS-A-agonist/antagonist.…”

Section: Trajectoriesmentioning

confidence: 99%

Investigating REV-ERBβ Binding Pocket Dynamics with Implications for Rational Design of Small Molecule Modulators

Srivastava,

Thakur,

Vishnu

et al. 2024

Preprint

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REV-ERBβ is a nuclear receptor (NR) with heme as an endogenous ligand that regulates its transcriptional activity. With key role in cellular functions such as glucose metabolism, immune response, and dysregulation in pathologies such as Type-2 diabetes mellitus and obesity, small molecules targeting REV-ERBs have been discovered with agonist and antagonistic effect. However, due to lack of crystal structures in complex with these compounds, the structural and dynamical basis of these activities still remains elusive and hinders rational design of molecules targeting REV-ERB. Using molecular dynamics simulations and docking studies, we have characterized the dynamics of REV-ERBβ ligand-binding domain (LBD) in different conformational states. The heme binding pocket within LBD remained closed in absence of a ligand and heme was found to stabilize its dynamics as well as nuclear co-repressor (NCoR) peptide binding. We further show that the binding of antagonist destabilizes the NCoR peptide binding to LBD, mediated by loss of interactions with residues at the REV-ERBβ-NCoR interface. These findings could be utilized to design molecular scaffolds with better activity and selectivity against REV-ERBβ.

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“…One exception, however, is efavirenz, which has been shown to induce sleep disorders and detrimental psychiatric symptoms in patients and to promote neurodegenerative effects in vitro and in vivo 20,31–34 . In addition, NNRTIs display one of the lower barriers to resistance among cART components 41,42 . Viral entry inhibitors also tend to be well tolerated, although they carry a slight risk of hepatotoxicity 13,43,44 .…”

Section: Introductionmentioning

confidence: 99%

Nucleoside reverse transcriptase inhibitors are the major class of HIV antiretroviral therapeutics that induce neuropathic pain in mice

Bush

Wairkar

Tang

2022

Preprint

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The development of combination antiretroviral therapy (cART) has transformed human immunodeficiency virus (HIV) infection from a lethal diagnosis into a chronic disease, and people living with HIV on cART can experience an almost normal life expectancy. However, these individuals often develop various complications that lead to decreased quality of life, one of the most significant of which is neuropathic pain and development of painful peripheral sensory neuropathy (PSN). Critically, although cART is thought to induce pain pathogenesis, the relative contribution of different classes of antiretrovirals has not been systematically investigated. In this study, we measured development of pathological pain and peripheral neuropathy in mice orally treated with distinct antiretrovirals at their translational dosages. Our results show that only nucleoside reverse transcriptases (NRTIs), but not other types of antiretrovirals, such as proteinase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase strand transfer inhibitors, and CCR5 antagonists, induce pathological pain and PSN. Thus, these findings suggest that NRTIs are the major class of antiretrovirals in cART that promote development of neuropathic pain. As NRTIs form the essential backbone of multiple different current cART regimens, it is of paramount clinical importance to better understand the underlying mechanism to facilitate design of less toxic forms of these drugs and or potential mitigation strategies.

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Small Conformational Changes Underlie Evolution of Resistance to NNRTI in HIV Reverse Transcriptase

Cited by 5 publications

References 53 publications

Probing structural basis for enhanced binding of SARS‐CoV‐2 P.1 variant spike protein with the human ACE2 receptor

Probing structural basis for enhanced binding of SARS‐CoV‐2 P.1 variant spike protein with the human ACE2 receptor

Investigating REV-ERBβ Binding Pocket Dynamics with Implications for Rational Design of Small Molecule Modulators

Nucleoside reverse transcriptase inhibitors are the major class of HIV antiretroviral therapeutics that induce neuropathic pain in mice

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