Organic cation transporter 3 (Oct3) is a distinct catecholamines clearance route in adipocytes mediating the beiging of white adipose tissue

Published date : 17 Jan 2019

Beiging of white adipose tissue (WAT) is a particularly appealing target for therapeutics in the treatment of metabolic diseases through norepinephrine (NE)-mediated signaling pathways. Although previous studies report NE clearance mechanisms via SLC6A2 on sympathetic neurons or proinflammatory macrophages in adipose tissues (ATs), the low catecholamine clearance capacity of SLC6A2 may limit the cleaning efficiency.

type
Journal Paper
journal
PLOS Biology, January 17 2019, doi: 10.1371/journal.pbio.2006571
Impact Factor
9.163

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

Perspective: The promises of a hilistic view of proteins - impact on antibody engineering and drug discovery

Published date : 10 Jan 2019

The reductionist approach is prevalent in biomedical science. However, increasing evidence now shows that biological systems cannot be simply considered as the sum of its parts. With experimental, technological and computational advances, we can now do more than view parts in isolation, thus wepropose that an increasing holistic view (where a protein is investigated as much as a whole as possible) is now timely. To further advocate this, we review and discuss several studies and applications involving allostery,where distant protein regions can cross-talk to influence functionality.

type
Journal Paper
journal
Bioscience Reports, Jan 10, 2019, DOI: 10.1042/BSR20181958
Impact Factor
2.899

Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein

Published date : 07 Jan 2019

Stapled-peptides have emerged as an exciting class of molecules which can modulate protein–protein interactions. We have used a structure-guided approach to rationally develop a set of hydrocarbon stapled-peptides with high binding affinities and residence times against the oncogenic eukaryotic translation initiation factor 4E (eIF4E) protein. Crystal structures of these peptides in complex with eIF4E show that they form specific interactions with a region on the protein-binding interface of eIF4E which is distinct from the other well-established canonical interactions.

type
Journal Paper
journal
Chemical Science, 2019, doi: 10.1039/C8SC03759K
Impact Factor
9.063

Energetic Fingerprinting of Ligand Binding to Paralogous Proteins: The Case of the Apoptotic Pathway

Published date : 24 Dec 2018

Networks of biological molecules are key to cellular function, governing processes ranging from signal cascade propagation to metabolic pathway regulation. Genetic duplication processes give rise to sets of regulatory proteins that have evolved from a common ancestor, leading to interactomes whose dysregulation is often associated with disease. A better understanding of the determinants of specificity at 21 interfaces shared by functionally related proteins is crucial to the rational design of novel pharmacotherapeutic agents.

type
Journal Paper
journal
Journal of Chemical Inofrmation and Modeling, 2018 Dec 24. doi: 10.1021/acs.jcim.8b00765
Impact Factor
3.804

Individual immune selection pressure has limited impact on seasonal influenza virus evolution

Published date : 06 Dec 2018

Seasonal influenza viruses are subjected to strong selection as seen by the sequential replacement of existing viral populations on the emergence of new antigenic variants. However, the process of within-host de novo mutant generation and evolutionary selection that underlies these antigenic sweeps is poorly understood. Here, we investigate mutational patterns between evolutionarily closely related human seasonal influenza viruses using host age as a proxy for immune experience.

type
Journal Paper
journal
Nature Ecology & Evolution, 2018, doi: 10.1038/s41559-018-0741-x

Simple yet functional phosphate-loop proteins

Published date : 30 Nov 2018

Abundant and essential motifs, such as phosphate-binding loops (P-loops), are presumed to be the seeds of modern enzymes. The Walker-A P-loop is absolutely essential in modern NTPase enzymes, in mediating binding, and transfer of the terminal phosphate groups of NTPs. However, NTPase function depends on many additional active-site residues placed throughout the protein’s scaffold. Can motifs such as P-loops confer function in a simpler context?

type
Journal Paper
journal
Proceedings of the National Academy of Sciences of the United States of America, PNAS, doi: 10.1073/pnas.1812400115
Impact Factor
9.504

Engineering an Osmosensor by Pivotal Histidine Positioning within Disordered Helices

Published date : 29 Nov 2018

Histidine kinases (HKs) funnel diverse environmental stimuli into a single autophosphorylation event at a conserved histidine residue. The HK EnvZ is a global sensor of osmolality and cellular acid pH. In previous studies, we discovered that osmosensing in EnvZ was mediated through osmolyte-induced stabilization of the partially disordered helical backbone spanning the conserved histidine autophosphorylation site (His243).

type
Journal Paper
journal
Structure, 27, 1-13, Feb 5, doi: 10.1016/j.str.2018.10.012
Impact Factor
4.907

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.

type
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

The Geographic Variation of Surveillance and Zoonotic Spillover Potential of Influenza Viruses in Domestic Poultry and Swine

Published date : 27 Nov 2018

Background
Avian and swine influenza viruses circulate worldwide and pose threats to both animal and human health. The design of global surveillance strategies is hindered by information gaps on the geospatial variation in virus emergence potential and existing surveillance efforts.

type
Journal Paper
journal
Open Forum Infectious Diseases, Vol. 5, issue 12, 1 Dec 2018, doi: 10.1093/ofid/ofy318
Impact Factor
3.240