KANNAN SRINIVASARAGHAVAN

"Inhibiting S100B(ββ) for Activating Wild-Type p53: Design of Stapled Peptides"

Published date : 14 Mar 2019

S100B(ββ) is a member of the S100B protein family and is distributed in a cell-specific manner. Its levels are elevated in several cancers such as malignant melanoma and correlate directly with poor prognosis in patients. S100B(ββ) directly interacts with the tumor suppressor p53, inhibiting tetramerization and protein kinase C-dependent phosphorylation, consequently decreasing p53 DNA binding and transcriptional activity, and preventing apoptosis. Thus, S100B(ββ) is being pursued as a target for therapeutic inhibition.

type
Journal Paper
journal
ACS Omega 2019, 5, Pg 5335-5344, doi: 10.1021/acsomega.9b00097

An inter-subunit protein-peptide interface that stabilizes the specific activity and oligomerization of the AAA+ chaperone Reptin

Published date : 09 Mar 2019

Reptin is a member of the AAA+ superfamily whose members can exist in equilibrium between monomeric apo forms and ligand bound hexamers. Inter-subunit protein-protein interfaces that stabilize Reptin in its oligomeric state are not well-defined. A self-peptide binding assay identified a protein-peptide interface mapping to an inter-subunit “rim” of the hexamer bridged by Tyrosine-340. A Y340A mutation reduced ADP-dependent oligomer formation using a gel filtration assay, suggesting that Y340 forms a dominant oligomer stabilizing side chain.

type
Journal Paper
journal
Journal of Proteomics, Vol. 199, 2019, Pg 89-101 doi:10.1016/j.jprot.2019.02.012
Impact Factor
3.722

Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket

Published date : 15 Jan 2019

The DNA binding domain (DBD) of the tumor suppressor p53 is the site of several oncogenic mutations. A subset of these mutations lowers the unfolding temperature of the DBD. Unfolding leads to the exposure of a hydrophobic β-strand and nucleates aggregation which results in pathologies through loss of function and dominant negative/gain of function effects.

type
Journal Paper
journal
Nuclei Acids Research, 2019, doi: 10.1093/nar/gky1314
Impact Factor
11.561

Effects of Single Nucleotide Polymorphisms on the Binding of Afatinib to EGFR: A Potential Patient Stratification Factor Revealed by Modeling Studies

Published date : 27 Nov 2018

The anticancer drug afatinib has been found to be more effective at inhibiting the oncogenic EGFR mutant exon 19 deletion (19del) over the oncogenic EGFR mutant L858R. The underlying mechanism has been hypothesized to result from differences in structural constraints introduced by the mutations and stabilizing interactions afforded by a buried water molecule in 19del (Kannan S. et al. Scientific Reports 2017, 7: 1540). The COSMIC cancer database is mined for EGFR sequences to discover that several mutations in the form of Single Nucleotide Polymorphisms (SNPs) line this hydration cavity.

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The anticancer drug afatinib has been found to be more effective at inhibiting the oncogenic EGFR mutant exon 19 deletion (19del) over the oncogenic EGFR mutant L858R. The underlying mechanism has been hypothesized to result from differences in structural constraints introduced by the mutations and stabilizing interactions afforded by a buried water molecule in 19del (Kannan S. et al. Scientific Reports 2017, 7: 1540). The COSMIC cancer database is mined for EGFR sequences to discover that several mutations in the form of Single Nucleotide Polymorphisms (SNPs) line this hydration cavity. In this work, the effects of these SNPs on the affinity of afatinib for EGFRWT and oncogenic mutants EGFRL858R and EGFR19del were studied using Free Energy Perturbation and Thermodynamic Integration calculations. The simulations reveal that several SNPs have significant effects on the affinity of afatinib for the mutant EGFRs carrying the SNPs and may thus have clinical implications relating to emergence of resistance to afatinib, thus potentially impacting the choice of EGFR inhibitors in the clinic.
journal
Journal of Chemical Information and Modeling, 2018 Nov 27. doi: 10.1021/acs.jcim.8b00491
Impact Factor
3.804

Molecular basis for dengue virus broad cross-neutralization by humanized monoclonal antibody 513

Published date : 31 May 2018

Dengue is a widespread viral disease with 3.6 billion people at risk worldwide. Humanized monoclonal antibody (mAb) 513, currently undergoing clinical trials in Singapore, targets an epitope on the envelope protein domain III exposed at the surface of the viral particle. This antibody potently neutralizes all four dengue virus serotypes in a humanized mouse model that recapitulates human dengue infection, without signs of antibody-mediated enhancement of the disease.

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Journal Paper
journal
Scientific Reports, 2018 May 31;8(1):8449 doi: 10.1038/s41598-018-26800-y
Impact Factor
4.122

Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib

Published date : 08 May 2017

Small molecules targeting the EGFR tyrosine kinase domain have been used with some success at treating patients with non-small cell lung cancer driven by activating mutations in the kinase domain. The initial class of inhibitors displaced ATP noncovalently but were rendered ineffective due to the development of resistance mutations in the kinase domain. These were overcome by the development of covalent inhibitors such as afatinib which also bind in the ATP pocket.

type
Journal Paper
journal
Scientific Reports 7, Article no: 1540 (2017), doi:10.1038/s41598-017-01491-z
Impact Factor
4.259