Reversing allosteric communication: From detecting allosteric sites to inducing and tuning targeted allosteric response

Published date : 18 Jun 2018

The omnipresence of allosteric regulation together with the fundamental role of structural dynamics in this phenomenon have initiated a great interest to the detection of regulatory exosites and design of corresponding effectors.

type
Journal Paper
journal
PLoS Computational Biology, 18 Jun 2018, doi:10.1371/journal.pcbi.1006228
Impact Factor
3.955

Orthosteric and allosteric action of the C5a receptor antagonists

Published date : 11 Jun 2018

The C5a receptor (C5aR) is a G-protein-coupled receptor (GPCR) that can induce strong inflammatory response to the anaphylatoxin C5a. Targeting C5aR has emerged as a novel anti-inflammatory therapeutic method. However, developing potent C5aR antagonists as drugs has proven difficult. Here, we report two crystal structures of human C5aR in ternary complexes with the peptide antagonist PMX53 and a non-peptide antagonist, either avacopan or NDT9513727.

type
Journal Paper
journal
Natural Structural & Molecular Biology, Vol 25, June 2018, Pg 472-481, doi:10.1038/s41594-018-0067-z
Impact Factor
12.595

Allosteric Effects between the Antibody Constant and Variable Regions: A Study of IgA Fc Mutations on Antigen Binding

Published date : 08 Jun 2018

Therapeutic antibodies have shifted the paradigm of disease treatments from small molecules to biologics, especially in cancer therapy. Despite the increasing number of antibody candidates, much remains unknown about the antibody and how its various regions interact. Recent findings showed that the antibody constant region can govern localization effects that are useful in reducing side effects due to systemic circulation by the commonly used IgG isotypes. Given their localized mucosal effects, IgA antibodies are increasingly promising therapeutic biologics.

type
Journal Paper
journal
Antibodies 2018, 7(2), 20, doi: 10.3390/antib7020020

A Funneled Conformational Landscape Governs Flavivirus Fusion Peptide Interaction with Lipid Membranes

Published date : 06 Jun 2018

During host cell infection by flaviviruses such as dengue and Zika, acidic pH within the endosome triggers a conformational change in the envelope protein on the outer surface of the virion. This results in exposure of the ∼15 residue fusion peptide (FP) region, freeing it to induce fusion between the viral and endosomal membranes. A better understanding of the conformational dynamics of the FP in the presence of membranes, and the basis for its selectivity for anionic lipid species present within the endosome, would facilitate its therapeutic targeting with antiviral drugs and antibodies.

type
Journal Paper
journal
Journal of Chemical Theory and Computation, 2018 Jul 10;14(7):3920-3932. doi: 10.1021/acs.jctc.8b00438
Impact Factor
5.399

Influence of pH on the activity of thrombin-derived antimicrobial peptides

Published date : 06 Jun 2018

The wound environment is characterized by physiological pH changes. Proteolysis of thrombin by wound-derived proteases, such as neutrophil elastase, generates antimicrobial thrombin-derived C-terminal peptides (TCPs), such as HVF18 (HVFRLKKWIQKVIDQFGE). Presence of such TCPs in human wound fluids in vivo, as well as the occurrence of an evolutionarily conserved His residue in the primary amino acid sequence of TCPs, prompted us to investigate the pH-dependent antibacterial action of HVF18, as well as of the prototypic GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE).

type
Journal Paper
journal
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2018 Jun 6, doi: 10.1016/j.bbamem.2018.06.002
Impact Factor
3.438

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.

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

Biophysical studies and modelling indicate the binding preference of TAZ WW domain for LATS1 PPxY motif

Published date : 30 May 2018

The Hippo tumor suppressor pathway is an important regulator of cell proliferation and apoptosis, and signal transduction occurs through phosphorylation of the effector protein TAZ by the serine/threonine kinase LATS1/2. Here, we report the biophysical and computational studies to characterize the interaction between TAZ and LATS1/2 through WW domain-PPxY motif binding. We show that the TAZ WW domain exhibits a binding preference for the second of the two PPxY motifs of LATS1 in vitro.

type
Journal Paper
journal
Biochemical and Biophysical Research Communications, Vol. 502, Issue 3, 20 Jul 2018, Pg 307-312, PMID: 29787761, doi: 10.1016/j.bbrc.2018.05.127

Impact Factor
2.559

The architecture of the OmpC-MlaA complex sheds light on the maintenance of outer membrane lipid asymmetry in Escherichia coli

Published date : 30 May 2018

A distinctive feature of the Gram-negative bacterial cell envelope is the asymmetric outer membrane (OM), where lipopolysaccharides and phospholipids (PLs) reside in the outer and inner leaflets, respectively. This unique lipid asymmetry renders the OM impermeable to external insults, including antibiotics and bile salts. In Escherichia coli, the complex comprising osmoporin OmpC and the OM lipoprotein MlaA is believed to maintain lipid asymmetry by removing mislocalized PLs from the outer leaflet of the OM. How this complex performs this function is unknown.

type
Journal Paper
journal
The Journal of Biological Chemistry, 2018 Jul 20;293(29):11325-11340. doi: 10.1074/jbc.RA118.002441
Impact Factor
4.010

Plasma Ceramides as Prognostic Biomarkers and Their Arterial and Myocardial Tissue Correlates in Acute Myocardial Infarction

Published date : 30 May 2018

We identified a plasma signature of 11 C14 to C26 ceramides and 1 C16 dihydroceramide predictive of major adverse cardiovascular events in patients with acute myocardial infarction (AMI). Among patients undergoing coronary artery bypass surgery, those with recent AMI, compared with those without recent AMI, showed a significant increase in 5 of the signature’s 12 ceramides in plasma but not simultaneously-biopsied aortic tissue.

type
Journal Paper
journal
JACC: Basic to Translational Science, Vol. 3, Issue 2, April 2018, pg 163-175, doi: 10.1016/j.jacbts.2017.12.005
Impact Factor
0.844

Exome sequencing and rare variant analysis reveals multiple filaggrin mutations in Bangladeshi atopic eczema families and additional risk genes

Published date : 30 May 2018

Atopic eczema (AE) is a heterogeneous chronic inflammatory skin condition that affects approximately 15–20% of children worldwide (Nutten, 2015). The prevalence varies widely among different countries, between rural and urban areas within a single country, and particular Asian skin types are more sensitive to urban environments (Ben-Gashir et al., 2004; Krutmann et al., 2014; Nutten, 2015; Odhiambo et al., 2009).

type
Journal Paper
journal
Journal of Investigative Dermatology, May 2018, doi: 10.1016/j.jid.2018.05.013
Impact Factor
6.448