Biomolecular Modelling & Design Division

Kinetic and thermodynamic effects of phosphorylation on p53 binding to MDM2

Published date : 24 Jan 2019

p53 is frequently mutated in human cancers. Its levels are tightly regulated by the E3 ubiquitin ligase MDM2. The complex between MDM2 and p53 is largely formed by the interaction between the N-terminal domain of MDM2 and the N-terminal transactivation (TA) domain of p53 (residues 15-29). We investigated the kinetic and thermodynamic basis of the MDM2/p53 interaction by using wild-type and mutant variants of the TA domain. We focus on the effects of phosphorylation at positions Thr18 and Ser20 including their substitution with phosphomimetics.

type
Journal Paper
journal
Scientific Reports 9, Article no: 693 (2019). doi: 10.1038/s41598-018-36589-5
Impact Factor
4.122

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

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

Exploring chromatin hierarchical organization via Markov State Modelling

Published date : 31 Dec 2018

We propose a new computational method for exploring chromatin structural organization based on Markov State Modelling of Hi-C data represented as an interaction network between genomic loci. A Markov process describes the random walk of a traveling probe in the corresponding energy landscape, mimicking the motion of a biomolecule involved in chromatin function.

type
Journal Paper
journal
PLoS Computational Biology, 2018 Dec 31;14(12), doi: 10.1371/journal.pcbi.100668
Impact Factor
3.955

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

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

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