Krishna Deepak

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

Identification of FDA-approved drugs as novel allosteric inhibitors of human executioner caspases

Published date : 14 Sep 2018

The regulation of apoptosis is a tightly-coordinated process and caspases are its chief regulators. Of special importance are the executioner caspases, caspase-3/7, the activation of which irreversibly sets the cell on the path of death. Dysregulation of apoptosis, particularly an increased rate of cell death lies at the root of numerous human diseases. Although several peptide-based inhibitors targeting the homologous active site region of caspases have been developed, owing to their non-specific activity and poor pharmacological properties their use has largely been restricted.

type
Journal Paper
journal
Proteins: Structure, Function and Bioinformatics, 2018 Sep 8. doi: 10.1002/prot.25601
Impact Factor
2.274

Structures of the Human PGD2 Receptor CRTH2 Reveal Novel Mechanisms for Ligand Recognition

Published date : 13 Sep 2018

The signaling of prostaglandin D 2 (PGD 2) through G-protein-coupled receptor (GPCR) CRTH2 is a major pathway in type 2 inflammation. Compelling evidence suggests the therapeutic benefits of blocking CRTH2 signaling in many inflammatory disorders. Currently, a number of CRTH2 antagonists are under clinical investigation, and one compound, fevipiprant, has advanced to phase 3 clinical trials for asthma. Here, we present the crystal structures of human CRTH2 with two antagonists, fevipiprant and CAY10471.

type
Journal Paper
journal
Molecular Cell, 2018, doi: 10.1016/j.molcel.2018.08.009
Impact Factor
14.428

Calmidazolium chloride and its complex with serum albumin prevent Huntingtin exon1 aggregation

Published date : 06 Jul 2018

Huntington's disease (HD) is a genetic disorder caused by a CAG expansion mutation in Huntingtin gene leading to polyglutamine (polyQ) expansion in the N-terminus side of Huntingtin (Httex1) protein. Neurodegeneration in HD is linked to aggregates formed by Httex1 bearing expanded polyQ. Initiation and elongation steps of Httex1 aggregation are potential target steps for the discovery of therapeutic molecules, for yet untreatable and cruel, HD. Here we report Httex1 aggregation inhibition by calmidazolium chloride (CLC) by acting on the initial aggregation event.

type
Journal Paper
journal
Molecular Pharmaceutics, 2018, 15 (8), pp 3356–3368, doi:10.1021/acs.molpharmaceut.8b00380, PMID: 29979597

Impact Factor
4.556

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