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

Lipid accumulation facilitates mitotic slippage-induced adaptation to anti-mitotic drug treatment

Published date : 27 Nov 2018

Aberrant lipid accumulation is a hallmark of cancer known to contribute to its aggressiveness and malignancy. Emerging studies have demonstrated context-dependent changes in lipid metabolism during chemotherapy. However, there is little known regarding the mechanisms linking lipid metabolism to chemotherapy-induced cell fates. Here, we describe lipid accumulation in cells following antimitotic drug treatment. Cells arrested in mitosis, as well as cells that escaped mitotic arrest and underwent mitotic slippage, showed elevated cytoplasmic lipid droplets.

type
Journal Paper
journal
Cell Death Discovery 4, Article no: 109. 2018, doi: 10.1038/s41420-018-0127-5

Mechanism of Enhanced Immature Dengue Virus Attachment to Endosomal Membrane Induced by prM Antibody

Published date : 21 Nov 2018

Dengue virus (DENV) particles are released from cells in different maturation states. Fully immature DENV (immDENV) is generally non-infectious, but can become infectious when complexed with anti-precursor membrane (prM) protein antibodies. It is unknown how anti-prM antibody-coated particles can undergo membrane fusion since the prM caps the envelope (E) protein fusion loop. Here, we determined cryoelectron microscopy (cryo-EM) maps of the immDENV:anti-prM complex at different pH values, mimicking the extracellular (pH 8.0) or endosomal (pH 5.0) environments.

type
Journal Paper
journal
Structure 27, 1-15, Feb 5, 2019, doi: 10.1016/j.str.2018.10.009
Impact Factor
4.907

On the perturbation nature of allostery: sites, mutations, and signal modulation

Published date : 12 Nov 2018

Regardless of the diversity of systems, allosteic signalling is found to be always caused by perturbations. This recurring trait of allostery serves as a foundation for developing different experimental efforts and theoretical models for the studies of allosteric mechanisms. Among computational approaches considered here particular emphasis is given to the structure-based statistical mechanical model of allostery (SBSMMA), which allows one to study the causality and energetics of allosteric communication.

type
Journal Paper
journal
Current Opinion in Structural Biology, Vol. 56, June 2019, Pg 18-27, doi: 10.1016/j.sbi.2018.10.008
Impact Factor
7.179

A dual substrate-accessing mechanism of a major facilitator superfamily protein facilitates lysophospholipid flipping across the cell membrane

Published date : 29 Oct 2018

Lysophospholipid transporter (LplT) is a member of the major facilitator superfamily (MFS) present in many Gram-negative bacteria. LplT catalyzes flipping of lysophospholipids (LPLs) across the bacterial inner membrane, playing an important role in bacterial membrane homeostasis. We previously reported that LplT promotes both uptake of exogenous LPLs and intramembranous LPL flipping across the bilayer.

type
Journal Paper
journal
Journal of Biological Chemistry, 2018, October 29, doi: 10.1074/jbc.RA118.005548
Impact Factor
4.01

AlloMAPS: allosteric mutation analysis and polymorphism of signaling database

Published date : 26 Oct 2018

AlloMAPS database provides data on the causality and energetics of allosteric communication obtained with the structure-based statistical mechanical model of allostery (SBSMMA). The database contains data on allosteric signaling in three sets of proteins and protein chains: (i) 46 proteins with comprehensively annotated functional and allosteric sites; (ii) 1908 protein chains from PDBselect set of chains with low (<25%) sequence identity; (iii) 33 proteins with more than 50 known pathological SNPs in each molecule.

type
Journal Paper
journal
Nucleic Acis Research, 2018, Oct 26, doi:10.1093/nar/gky1028
Impact Factor
11.561

Influenza Vaccine-Induced Antibody Responses Are Not Impaired by Frailty in the Community-Dwelling Elderly With Natural Influenza Exposure

Published date : 24 Oct 2018

Background: Elderly adults over 65 years of age are recommended to receive seasonal influenza vaccination as they are at a higher risk of infection and its complications than the younger community. The elderly are often stratified according to frailty status where frail individuals are more susceptible to adverse health outcomes than their non-frail counterparts, however, it is not known whether immunity induced by influenza vaccination is impaired in the frail elderly.

type
Journal Paper
journal
Frontiers in Immunology, 24 Oct 2018, Vol. 9, Article 265, doi: 10.3389/fimmu.2018.02465
Impact Factor
5.511