LAMA Dilraj

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

Homologous Lympho-Epithelial Kazal-type Inhibitor Domains Delay Blood Coagulation by Inhibiting Factor X and XI with Differential Specificity

Published date : 12 Jul 2018

Despite being initially identified in the blood filtrate, LEKTI is a 15-domain Kazal-type inhibitor mostly known in the regulation of skin desquamation. In the current study, screening of serine proteases in blood coagulation cascade showed that LEKTI domain 4 has inhibitory activity toward only FXIa, whereas LEKTI domain 6 inhibits both FXIa and FXaB (bovine FXa). Nuclear magnetic resonance structural and dynamic experiments plus molecular dynamics simulation revealed that LEKTI domain 4 has enhanced backbone flexibility at the reactive-site loop.

type
Journal Paper
journal
Structure, 26, Pg 1178-1186, Sept 4, 2018, doi: 10.1016/j.str.2018.05.018, PMID: 30017565
Impact Factor
4.907

Water-Bridge Mediates Recognition of mRNA Cap in eIF4E

Published date : 01 Dec 2016

Ligand binding pockets in proteins contain water molecules, which play important roles in modulating protein-ligand interactions. Available crystallographic data for the 5′ mRNA cap-binding pocket of the translation initiation factor protein eIF4E shows several structurally conserved waters, which also persist in molecular dynamics simulations. These waters engage an intricate hydrogen-bond network between the cap and protein.

type
Journal Paper
journal
Structure 25, 1–7, January 3, 2017
Impact Factor
5.237

R248Q mutation – Beyond p53-DNA binding

Published date : 07 Oct 2015

R248 in the DNA binding domain (DBD) of p53 interacts directly with the minor groove of DNA. Earlier nuclear magnetic resonance studies indicated that the R248Q mutation resulted in conformation changes in parts of DBD far from the mutation site. However, how information propagates from the mutation site to the rest of the DBD is still not well understood.

type
Journal Paper
journal
Proteins: Structure, Function and Bioinformatics, 2015, doi: 10.1002/prot.24940
Impact Factor
2.627

USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination

Published date : 05 Oct 2015

Ubiquitin modification of the TGF-β pathway components is emerging as a key mechanism of TGF-β pathway regulation. To limit TGF-β responses, TGF-β signaling is regulated through a negative feedback loop whereby the E3 ligase SMURF2 targets the TGF-β receptor (TβR) complex for ubiquitin-mediated degradation. Counteracting this process, a number of deubiquitinating (DUBs) enzymes have recently been identified that deubiquitinate and stabilize the TβR. However

type
Journal Paper
journal
Scientific Reports 2015 Oct 5;5:14733. doi: 10.1038/srep14733
Impact Factor
5.578

Gating by Tryptophan 73 Exposes a Cryptic Pocket at the Protein-Binding Interface of the Oncogenic eIF4E Protein

Published date : 02 Oct 2015

Targeting protein-protein interacting sites for potential therapeutic applications is a challenge in the development of inhibitors, and this becomes more difficult when these interfaces are relatively planar, as in the eukaryotic translation initiation factor 4E (eIF4E) protein. eIF4E is an oncogene that is overexpressed in numerous forms of cancer, making it a prime target as a therapeutic molecule.

type
Journal Paper
journal
Biochemistry, 2015, 54 (42), pp 6535–6544 doi: 10.1021/acs.biochem.5b00812
Impact Factor
3.015

Evidence of a conserved intrinsically disordered region in the C-terminus of the sringent response protein Rel from mycobacteria

Published date : 06 Apr 2014

The RelA/SpoT enzyme produces (p)ppGpp that helps the bacterium survive during stress. The domains present in it are interspersed with connecting linkers whose functions have been poorly elucidated. We rationally analyzed the sequence and structural property of the regulatory C-terminal region in the Rel family of proteins and report the presence of an intrinsically disordered region between two successive domains in this region that are separated by a defined amino acid sequence length.

type
Journal Paper
journal
FEBS Letters 2014, doi: 10.1016/j.febslet.2014.03.048
Impact Factor
3.56

Rational Optimization of Conformational Effects Induced By Hydrocarbon Staples in Peptides and their Binding Interfaces

Published date : 13 Dec 2013

eIF4E is frequently over-expressed in different cancers and causes increased translation of oncogenic proteins via deregulated cap-dependent translation. Inhibitors of the eIF4E:eIF4G interactions represent an approach that would normalize cap-dependent translation. Stapled peptides represent an emerging class of therapeutics that can target protein: protein interactions. We present here molecular dynamics simulations for a set of rationally designed stapled peptides in solution and in complex with eIF4E, supported with biophysical and crystallographic data.

type
Journal Paper
journal
Scientific Reports 2013, 3:3451, doi: 10.1038/srep03451
Impact Factor
2.927