Lokender Kumar

Shoolini University

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Judith Klein‐Seetharaman

Arizona State University

Susanta K. Sarkar

University of Kalyani

Sanjay Chhibber

Panjab University

Kusum Harjai

Panjab University

Chase Harms

Colorado School of Mines

Nastassja A. Lewinski

Virginia Commonwealth University

Deepak Kumar

Shoolini University

Derek Wright

University of Regina

Jinkyu Yang

American Institute of Aeronautics and Astronautics

Liza M. Roger

Virginia Commonwealth University

Cooperative Institutions

Shoolini University

Colorado School of Mines

University of Würzburg

Tufts University

Panjab University

Helmholtz Zentrum München

Universidade de São Paulo

Banaras Hindu University

Guru Jambheshwar University of Science and Technology

Chandigarh University

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7-Dehydrocholesterol is an endogenous suppressor of ferroptosis

Nature (2024)

Florêncio Porto Freitas Hamed Alborzinia Ancély Ferreira dos Santos Palina Nepachalovich Lohans Pedrera

10.1038/s41586-023-06878-9

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Citations (102)

Structure‐based survey of ligand binding in the human insulin receptor

British Journal of Pharmacology (2021)

Lokender Kumar Whitney Vizgaudis Judith Klein‐Seetharaman

The insulin receptor is a membrane protein responsible for the regulation of nutrient balance; and therefore, it is an attractive target in the treatment of diabetes and metabolic syndrome. Pharmacology of the insulin receptor involves two distinct mechanisms: (1) activation of the receptor by insulin mimetics that bind in the extracellular domain and (2) inhibition of the receptor TK enzymatic activity in the cytoplasmic domain. While a complete structural picture of the full‐length receptor comprising the entire sequence covering extracellular, transmembrane, juxtamembrane and cytoplasmic domains is still elusive, recent progress through cryoelectron microscopy has made it possible to describe the initial insulin ligand binding events at atomistic detail. We utilize this opportunity to obtain structural insights into the pharmacology of the insulin receptor. To this end, we conducted a comprehensive docking study of known ligands to the new structures of the receptor. Through this approach, we provide an in‐depth, structure‐based review of human insulin receptor pharmacology in light of the new structures. LINKED ARTICLES This article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.14/issuetoc

Structural Biology

Docking (animal)

10.1111/bph.15777

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Citations (7)

Identification of allosteric fingerprints of alpha-synuclein aggregates in matrix metalloprotease-1 and substrate-specific virtual screening with single molecule insights

Scientific Reports (2022)

Sumaer Kamboj Chase Harms Derek Wright Anthony Nash Lokender Kumar

Abstract Alpha-synuclein (aSyn) has implications in pathological protein aggregations in neurodegeneration. Matrix metalloproteases (MMPs) are broad-spectrum proteases and cleave aSyn, leading to aggregation. Previous reports showed that allosteric communications between the two domains of MMP1 on collagen fibril and fibrin depend on substrates, activity, and ligands. This paper reports quantification of allostery using single molecule measurements of MMP1 dynamics on aSyn-induced aggregates by calculating Forster Resonance Energy Transfer (FRET) between two dyes attached to the catalytic and hemopexin domains of MMP1. The two domains of MMP1 prefer open conformations that are inhibited by a single point mutation E219Q of MMP1 and tetracycline, an MMP inhibitor. A two-state Poisson process describes the interdomain dynamics, where the two states and kinetic rates of interconversion between them are obtained from histograms and autocorrelations of FRET values. Since a crystal structure of aSyn-bound MMP1 is unavailable, binding poses were predicted by molecular docking of MMP1 with aSyn using ClusPro. MMP1 dynamics were simulated using predicted binding poses and compared with the experimental interdomain dynamics to identify an appropriate pose. The selected aSyn-MMP1 binding pose near aSyn residue K45 was simulated and analyzed to define conformational changes at the catalytic site. Allosteric residues in aSyn-bound MMP1 exhibiting strong correlations with the catalytic motif residues were compared with allosteric residues in free MMP1, and aSyn-specific residues were identified. The allosteric residues in aSyn-bound MMP1 are K281, T283, G292, G327, L328, E329, R337, F343, G345, N346, Y348, G353, Q354, D363, Y365, S366, S367, F368, P371, R372, V374, K375, A379, F391, A394, R399, M414, F419, V426, and C466. Shannon entropy was defined to quantify MMP1 dynamics. Virtual screening was performed against a site on selected aSyn-MMP1 binding poses, which showed that lead molecules differ between free MMP1 and substrate-bound MMP1. Also, identifying aSyn-specific allosteric residues in MMP1 enabled further selection of lead molecules. In other words, virtual screening needs to take substrates into account for potential substrate-specific control of MMP1 activity in the future. Molecular understanding of interactions between MMP1 and aSyn-induced aggregates may open up the possibility of degrading aggregates by targeting MMPs.

MMP1

10.1038/s41598-022-09866-7

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Citations (3)

Insulin Signaling and Pharmacology in Corals

Authorea (Authorea) (2024)

Whitney Vizgaudis Lokender Kumar Monsurat Olaosebikan Liza M. Roger Nathanael Brenner

Once thought to be a unique capability of the Langerhans Islands in the pancreas of mammals, insulin production is now recognized as an evolutionarily ancient function going back to prokaryotes, ubiquitously present in unicellular eukaryotes, fungi, worm, Drosophila and of course human. While the functionality of the signaling pathway has been experimentally demonstrated in some of these organisms, it has not yet been exploited for pharmacological applications. To enable such applications, we need to understand the extent to which the structure and function of the insulin-insulin receptor system is conserved. To this end, we analyzed the insulin signaling pathway in corals through remote homology detection and modeling. By docking known insulin receptor ligands to a coral homology structure, we locate ligand binding pockets and demonstrate their conservation suggesting that it may be possible to exploit the structural conservation for pharmacological applications in non-model organisms. We also identified the coral homologues of the over 100 signaling proteins involved in insulin and its related signaling pathways, demonstrating their wide-spread conservation. Notable exceptions are glucagon and somatostatin. It is tempting to speculate that under high light conditions, when the algae synthetize excess sugars, the cnidarian host may experience insulin resistance, and that the cnidarian microbiome may be involved in manipulating the insulin signaling system.

10.22541/au.170666200.07483513/v1

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Allosteric Communications between Domains Modulate the Activity of Matrix Metalloprotease-1

Biophysical Journal (2020)

Lokender Kumar Anthony Nash Chase Harms Joan Planas-Iglesias Derek Wright

An understanding of the structure-dynamics relationship is essential for understanding how a protein works. Prior research has shown that the activity of a protein correlates with intradomain dynamics occurring at picosecond to millisecond timescales. However, the correlation between interdomain dynamics and the function of a protein is poorly understood. Here, we show that communications between the catalytic and hemopexin domains of matrix metalloprotease-1 (MMP1) on type 1 collagen fibrils correlate with its activity. Using single-molecule Förster resonance energy transfer, we identified functionally relevant open conformations in which the two MMP1 domains are well separated, which were significantly absent for catalytically inactive point mutant (E219Q) of MMP1 and could be modulated by an inhibitor or an enhancer of activity. The observed relevance of open conformations resolves the debate about the roles of open and closed MMP1 structures in function. We fitted the histograms of single-molecule Förster resonance energy transfer values to a sum of two Gaussians and the autocorrelations to an exponential and power law. We used a two-state Poisson process to describe the dynamics and calculate the kinetic rates from the fit parameters. All-atom and coarse-grained simulations reproduced some of the experimental features and revealed substrate-dependent MMP1 dynamics. Our results suggest that an interdomain separation facilitates opening up the catalytic pocket so that the collagen chains come closer to the MMP1 active site. Coordination of functional conformations at different parts of MMP1 occurs via allosteric communications that can take place via interactions mediated by collagen even if the linker between the domains is absent. Modeling dynamics as a Poisson process enables connecting the picosecond timescales of molecular dynamics simulations with the millisecond timescales of single-molecule measurements. Water-soluble MMP1 interacting with water-insoluble collagen fibrils poses challenges for biochemical studies that the single-molecule tracking can overcome for other insoluble substrates. Interdomain communications are likely important for multidomain proteins.

MMP1

10.1016/j.bpj.2020.06.010

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Citations (16)

Insulin signaling and pharmacology in humans and in corals

PeerJ (2024)

Meghana Murthy Paniz Jasbi Whitney Lowe Lokender Kumar Monsurat Olaosebikan

Once thought to be a unique capability of the Langerhans islets in the pancreas of mammals, insulin (INS) signaling is now recognized as an evolutionarily ancient function going back to prokaryotes. INS is ubiquitously present not only in humans but also in unicellular eukaryotes, fungi, worms, and Drosophila . Remote homologue identification also supports the presence of INS and INS receptor in corals where the availability of glucose is largely dependent on the photosynthetic activity of the symbiotic algae. The cnidarian animal host of corals operates together with a 20,000-sized microbiome, in direct analogy to the human gut microbiome. In humans, aberrant INS signaling is the hallmark of metabolic disease, and is thought to play a major role in aging, and age-related diseases, such as Alzheimer’s disease. We here would like to argue that a broader view of INS beyond its human homeostasis function may help us understand other organisms, and in turn, studying those non-model organisms may enable a novel view of the human INS signaling system. To this end, we here review INS signaling from a new angle, by drawing analogies between humans and corals at the molecular level.

Model Organism

10.7717/peerj.16804

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Citations (1)

Structure-based survey of ligand binding in the human insulin receptor

Authorea (Authorea) (2021)

Judith Klein‐Seetharaman Whitney Vizgaudis Lokender Kumar

The insulin receptor is a membrane protein responsible for regulation of nutrient balance and therefore an attractive target in the treatment of diabetes and metabolic syndrome. Pharmacology of the insulin receptor involves two distinct mechanisms, (1) activation of the receptor by insulin mimetics that bind in the extracellular domain and (2) inhibition of the receptor tyrosine kinase enzymatic activity in the cytoplasmic domain. While a complete structural picture of the full-length receptor comprising the entire sequence covering extracellular, transmembrane, juxtamembrane and cytoplasmic domains is still elusive, recent progress through cryoelectron microscopy has made it possible to describe the initial insulin ligand binding events at atomistic detail. We utilize this opportunity to obtain structural insights into the pharmacology of the insulin receptor. To this end, we conducted a comprehensive docking study of known ligands to the new structures of the receptor. Through this approach, we provide an in-depth, structure-based review of human insulin receptor pharmacology in light of the new structures.

Docking (animal)

10.22541/au.162245427.70273837/v1

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Citations (0)

Hepatoprotective Effect of Zingerone (4-(4-Hydroxy-3- Methoxyphenyl) Butan-2-One) in Lipopolysaccharide Induced Liver Injury Mouse Model through Downregulation of Inflammatory Mediators

Lokender Kumar Sanjay Chhibber Kusum Harjai

Lipopolysaccharide (LPS) is responsible for causing inflammation leading to septic shock or organ failure. During treatment of infection, h igh amount of LPS is released in blood circulation due to immediate lysis of bacteria. Since liver helps in clearing LPS from the body, hence it remains the primary target to be stimulated by LPS releasing vigorous amount of inflammatory molecules leading to liver injury. Available anti -inflammatory chemotherapy fails in such situation because it relies predominantly on specific or non specific inhibitors of cyclooxygenase enzyme activity (COX -2) with broad range of hepatic, renal and cardiovascular side effects. There is a need to replace the potential therapies targeting suppression of LPS induced inflammation with those having no or minimal side effects. Active components from dietary medicinal plants like ginger ( Zingiber officinale) are potential source of non toxic antioxidant as well as anti -inflammatory molecules. In the present study, protective effect of zingerone was evaluated against inflammation induced by LPS in terms of liver histology, serum endotoxin levels, liver function markers (AST, ALT, ALP) and inflammatory mediators (malondialdehyde, reactive nitrogen intermediates, myeloperoxidase). Relative mRNA expression of LPS induced inflammatory markers TLR4, TNF- and iNOS was also evaluated in zingerone treated and untreated groups . Hepatoprotective effect of zingerone was observed leading to significant improvement in liver histology , decreased levels of serum endotoxin levels, liver function markers and MPO, MDA, RNI. It also showed significant down regulation of mRNA expression of TLR4, TNF- and iNOS suggesting potent anti-inflammatory activity of zingerone against P.aeruginosa LPS induced liver injury.

Malondialdehyde

Liver function

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Citations (14)

Applying model approaches in non-model systems: A review and case study on coral cell culture

PLoS ONE (2021)

Liza M. Roger Hannah Reich Evan Lawrence Shuaifeng Li Whitney Vizgaudis

Model systems approaches search for commonality in patterns underlying biological diversity and complexity led by common evolutionary paths. The success of the approach does not rest on the species chosen but on the scalability of the model and methods used to develop the model and engage research. Fine-tuning approaches to improve coral cell cultures will provide a robust platform for studying symbiosis breakdown, the calcification mechanism and its disruption, protein interactions, micronutrient transport/exchange, and the toxicity of nanoparticles, among other key biological aspects, with the added advantage of minimizing the ethical conundrum of repeated testing on ecologically threatened organisms. The work presented here aimed to lay the foundation towards development of effective methods to sort and culture reef-building coral cells with the ultimate goal of obtaining immortal cell lines for the study of bleaching, disease and toxicity at the cellular and polyp levels. To achieve this objective, the team conducted a thorough review and tested the available methods (i.e. cell dissociation, isolation, sorting, attachment and proliferation). The most effective and reproducible techniques were combined to consolidate culture methods and generate uncontaminated coral cell cultures for ~7 days (10 days maximum). The tests were conducted on scleractinian corals Pocillopora acuta of the same genotype to harmonize results and reduce variation linked to genetic diversity. The development of cell separation and identification methods in conjunction with further investigations into coral cell-type specific metabolic requirements will allow us to tailor growth media for optimized monocultures as a tool for studying essential reef-building coral traits such as symbiosis, wound healing and calcification at multiple scales.

Scleractinia

10.1371/journal.pone.0248953

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Citations (18)

Exploring The Interrelation Between Indoor Bacterial Burden And The Physicochemical Dynamics Of Indoor Air Quality In Public Commercial Edifices

Yogyata Srivastava Abhishek Chauhan Lokender Kumar Tanu Jindal

Dynamics

10.53555/kuey.v30i4.1585

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Citations (0)