Tapan Kumar Nayak

Scopus Publications

Mechanism of hydrophobic gating in the acetylcholine receptor channel pore
Monika Kumari, Nadira Khatoon, Rachita Sharma, Sushanth Adusumilli, Anthony Auerbach, Hemant K. Kashyap, Tapan K. Nayak
Journal of General Physiology, 2024
Neuromuscular acetylcholine receptors (AChRs) are hetero-pentameric, ligand-gated ion channels. The binding of the neurotransmitter acetylcholine (ACh) to two target sites promotes a global conformational change of the receptor that opens the channel and allows ion conduction through the channel pore. Here, by measuring free-energy changes from single-channel current recordings and using molecular dynamics simulations, we elucidate how a constricted hydrophobic region acts as a “gate” to regulate the channel opening in the pore of AChRs. Mutations of gate residues, including those implicated in congenital myasthenia syndrome, lower the permeation barrier of the channel substantially and increase the unliganded gating equilibrium constant (constitutive channel openings). Correlations between hydrophobicity and the observed free-energy changes, supported by calculations of water densities in the wild-type versus mutant channel pores, provide evidence for hydrophobic wetting–dewetting transition at the gate. The analysis of a coupled interaction network provides insight into the molecular mechanism of closed- versus open-state conformational changes at the gate. Studies of the transition state by “phi”(φ)-value analysis indicate that agonist binding serves to stabilize both the transition and the open state. Intersubunit interaction energy measurements and molecular dynamics simulations suggest that channel opening involves tilting of the pore-lining M2 helices, asymmetric outward rotation of amino acid side chains, and wetting transition of the gate region that lowers the barrier to ion permeation and stabilizes the channel open conformation. Our work provides new insight into the hydrophobic gate opening and shows why the gate mutations result in constitutive AChR channel activity.
Genomic and transcriptomic applications in neural stem cell therapeutics
Sushanth Adusumilli, Manvee Chauhan, Mahesh Mahadeo Mathe, Tapan Kumar Nayak, Jayasha Shandilya
Computational Biology for Stem Cell Research, 2024
Bispidine as a Versatile Scaffold: From Topological Hosts to Transmembrane Transporters
Hanuman Singh, Nadira Khatoon, Surya Kant Bhardwaj, Pradeepti Kampani, Tapan K. Nayak, V. Haridas
Chembiochem, 2023
The development of designer topological structures is a synthetically challenging endeavor. We present herein bispidine as a platform for the design of molecules with various topologies and functions. The bispidine‐based acyclic molecule, which shows intriguing S‐shape topology, is discussed. Single‐crystal X‐ray diffraction studies revealed that this molecule exists in the solid state as two conformational enantiomers. In addition, bispidine‐based designer macrocycles were synthesized and investigated for ionophoric properties. Patch clamp experiments revealed that these macrocycles transport both anions and cations non‐specifically with at least tenfold higher chloride conductance over the cations under the given experimental conditions. Ultramicroscopy and single‐crystal X‐ray crystallographic studies indicated that the self‐assembling macrocycle forms a tubular assembly. Our design highlights the use of unconventional dihydrogen interactions in nanotube fabrication.
Protein engineering and design in ion channels and receptors
Nadira Khatoon, Sushanth Adusumilli, Poulomi Dey, Rachita Sharma, Pradeepti Kampani, Jayasha Shandilya, Tapan K. Nayak
Methods in Cell Biology, 2022
Erratum: Efficiency measures the conversion of agonist binding energy into receptor conformational change (Journal of General Physiology (2019)151: 4Doi: 10.1085/jgp.201812215)
T. Nayak, Ridhima Vij, Iva Bruhova, Jayasha Shandilya, A. Auerbach
Journal of General Physiology, 2020
iPSC model of CHRFAM7A effect on α7 nicotinic acetylcholine receptor function in the human context
I. Ihnatovych, T. Nayak, A. Ouf, N. Sule, B. Birkaya, L. Chaves, A. Auerbach, K. Szigeti
Translational Psychiatry, 2019
The α7 nicotinic acetylcholine receptor (α7nAChR) has been a promising target for diseases affecting cognition and higher cortical functions; however, the effect observed in animal models failed to translate into human clinical trials identifying a translational gap. CHRFAM7A is a human-specific fusion gene with properties that enable incorporation into the α7nAChR and, being human specific, CHRFAM7A effect was not accounted for in preclinical studies. We hypothesized that CHRFAM7A may account for this translational gap and understanding its function may offer novel insights when exploring α7nAChR as a drug target. CHRFAM7A is present in different copy number variations (CNV) in the human genome with high frequency. To study the functional consequences of the presence of the CHRFAM7A, two induced pluripotent stem cell (iPSC) lines (0 copy and 1 copy direct) were developed. The 0 copy line was rescued with CHRFAM7A transfection to control for genetic heterogeneity. As readouts for genotype–phenotype correlation, α7nAChR synaptic transmission and amyloid beta 1–42 (Aβ1–42) uptake were tested. Synaptic transmission in the presence of CHRFAM7A demonstrated that PNU-modulated desensitization of α7nAChR currents increased as a function of CHRFAM7A dosage. CHRFAM7A mitigated the dose response of Aβ1–42 uptake suggesting a protective effect beyond physiological concentrations. Furthermore, in the presence of CHRFAM7A Aβ1–42 uptake activated neuronal interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) without activating the canonical inflammasome pathway. Lead optimization may identify more potent molecules when the screen has a model harboring CHRFAM7A. Incorporating pharmacogenetics into clinical trials may enhance signals in efficacy measures.
Efficiency measures the conversion of agonist binding energy into receptor conformational change
T. Nayak, Ridhima Vij, Iva Bruhova, Jayasha Shandilya, A. Auerbach
Journal of General Physiology, 2019
Receptors alternate between resting↔active conformations that bind agonists with low↔high affinity. Here, we define a new agonist attribute, energy efficiency (&eegr;), as the fraction of ligand-binding energy converted into the mechanical work of the activation conformational change. &eegr; depends only on the resting/active agonist-binding energy ratio. In a plot of activation energy versus binding energy (an “efficiency” plot), the slope gives &eegr; and the y intercept gives the receptor’s intrinsic activation energy (without agonists; &Dgr;G0). We used single-channel electrophysiology to estimate &eegr; for eight different agonists and &Dgr;G0 in human endplate acetylcholine receptors (AChRs). From published equilibrium constants, we also estimated &eegr; for agonists of KCa1.1 (BK channels) and muscarinic, &ggr;-aminobutyric acid, glutamate, glycine, and aryl-hydrocarbon receptors, and &Dgr;G0 for all of these except KCa1.1. Regarding AChRs, &eegr; is 48–56% for agonists related structurally to acetylcholine but is only ∼39% for agonists related to epibatidine; &Dgr;G0 is 8.4 kcal/mol in adult and 9.6 kcal/mol in fetal receptors. Efficiency plots for all of the above receptors are approximately linear, with &eegr; values between 12% and 57% and &Dgr;G0 values between 2 and 12 kcal/mol. Efficiency appears to be a general attribute of agonist action at receptor binding sites that is useful for understanding binding mechanisms, categorizing agonists, and estimating concentration–response relationships.
Cyclic activation of endplate acetylcholine receptors
T. Nayak, A. Auerbach
Proceedings of the National Academy of Sciences of the United States of America, 2017
Significance The binding of agonists to receptors is an essential event in cell signaling. We propose a general mechanism for agonist binding based on a model allosteric protein, the neuromuscular acetylcholine receptor. Binding constants were measured for different agonists, to both resting and active individual target sites. The results confirm a cyclic activation mechanism. Agonist binding requires diffusion and a local conformational change, with receptor activation accelerating the latter so that association becomes nearly diffusion-limited. At each site, receptor activation approximately doubles the agonist-binding energy. These results indicate that binding (“affinity”) and activation (“efficacy”), long considered to be independent processes, are linked obligatorily. We speculate that cyclic activation and coupling between activation and binding are fundamental aspects of receptor operation. Agonists turn on receptors because they have a higher affinity for active versus resting conformations of the protein. Activation can occur by either of two pathways that connect to form a cycle: Agonists bind to resting receptors that then become active, or resting receptors activate and then bind agonists. We used mutations to construct endplate acetylcholine receptors (AChRs) having only one functional neurotransmitter-binding site and single-channel electrophysiology to measure independently binding constants for four different agonists, to both resting and active conformations of each site. For all agonists and sites, the total free energy change in each pathway was the same, confirming the activation cycle without external energy. Other results show that (i) there is no cooperativity between sites; (ii) agonist association is slower than diffusion in resting receptors but nearly diffusional in active receptors; (iii) whereas resting affinity is determined mainly by agonist association, active affinity is determined mainly by agonist dissociation; and (iv) at each site and for all agonists, receptor activation approximately doubles the agonist-binding free energy. We discuss a two-step mechanism for binding that involves diffusion and a local conformational change (“catch”) that is modulated by receptor activation. The results suggest that binding to a resting site and the switch to high affinity are both integral parts of a single allosteric transition. We hypothesize that catch ensures proper signal recognition in complex chemical environments and that binding site compaction is a determinant of both resting and active affinity.
Acute tumour response to a bispecific Ang-2-VEGF-A antibody: Insights from multiparametric MRI and gene expression profiling
L. C. Baker, J. Boult, Markus Thomas, A. Koehler, T. Nayak, J. Tessier, C. Ooi, F. Birzele, A. Belousov, M. Zając, Carsten Horn, Clare V Lefave, S. Robinson
British Journal of Cancer, 2016
Background:To assess antivascular effects, and evaluate clinically translatable magnetic resonance imaging (MRI) biomarkers of tumour response in vivo, following treatment with vanucizumab, a bispecific human antibody against angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A).Methods:Colo205 colon cancer xenografts were imaged before and 5 days after treatment with a single 10 mg kg−1 dose of either vanucizumab, bevacizumab (anti-human VEGF-A), LC06 (anti-murine/human Ang-2) or omalizumab (anti-human IgE control). Volumetric response was assessed using T2-weighted MRI, and diffusion-weighted, dynamic contrast-enhanced (DCE) and susceptibility contrast MRI used to quantify tumour water diffusivity (apparent diffusion coefficient (ADC), × 106 mm2 s−1), vascular perfusion/permeability (Ktrans, min−1) and fractional blood volume (fBV, %) respectively. Pathological correlates were sought, and preliminary gene expression profiling performed.Results:Treatment with vanucizumab, bevacizumab or LC06 induced a significant (P<0.01) cytolentic response compared with control. There was no significant change in tumour ADC in any treatment group. Uptake of Gd-DTPA was restricted to the tumour periphery in all post-treatment groups. A significant reduction in tumour Ktrans (P<0.05) and fBV (P<0.01) was determined 5 days after treatment with vanucizumab only. This was associated with a significant (P<0.05) reduction in Hoechst 33342 uptake compared with control. Gene expression profiling identified 20 human genes exclusively regulated by vanucizumab, 6 of which are known to be involved in vasculogenesis and angiogenesis.Conclusions:Vanucizumab is a promising antitumour and antiangiogenic treatment, whose antivascular activity can be monitored using DCE and susceptibility contrast MRI. Differential gene expression in vanucizumab-treated tumours is regulated by the combined effect of Ang-2 and VEGF-A inhibition.
Structural correlates of affinity in fetal versus adult endplate nicotinic receptors
T. Nayak, Srirupa Chakraborty, W. Zheng, A. Auerbach
Nature Communications, 2016
Adult-type nicotinic acetylcholine receptors (AChRs) mediate signalling at mature neuromuscular junctions and fetal-type AChRs are necessary for proper synapse development. Each AChR has two neurotransmitter binding sites located at the interface of a principal and a complementary subunit. Although all agonist binding sites have the same core of five aromatic amino acids, the fetal site has ∼30-fold higher affinity for the neurotransmitter ACh. Here we use molecular dynamics simulations of adult versus fetal homology models to identify complementary-subunit residues near the core that influence affinity, and use single-channel electrophysiology to corroborate the results. Four residues in combination determine adult versus fetal affinity. Simulations suggest that at lower-affinity sites, one of these unsettles the core directly and the others (in loop E) increase backbone flexibility to unlock a key, complementary tryptophan from the core. Swapping only four amino acids is necessary and sufficient to exchange function between adult and fetal AChRs.
Isolation and 111In-Oxine Labeling of Murine NK Cells for Assessment of Cell Trafficking in Orthotopic Lung Tumor Model
G. Malviya, T. Nayak, C. Gerdes, R. Dierckx, A. Signore, E. D. de Vries
Molecular Pharmaceutics, 2016
Synthesis and preliminary biological evaluations of fluorescent or 149Promethium labeled Trastuzumab-polyethylenimine
J. Fitzsimmons, T. Nayak, C. Cutler, R. Atcher
Biomedicines, 2016
Monitoring therapy response of experimental arthritis with radiolabeled tracers targeting fibroblasts, macrophages, or integrin αvβ3
S. Terry, M. Koenders, G. Franssen, T. Nayak, A. Freimoser-Grundschober, C. Klein, W. Oyen, O. Boerman, P. Laverman
Journal of Nuclear Medicine, 2016
AP1 transcription factors are required to maintain the peripheral taste system
Jayasha Shandilya, Yankun Gao, T. Nayak, S. Roberts, K. Medler
Cell Death and Disease, 2016
Therapy response monitoring of the early effects of a new BRAF inhibitor on melanoma xenograft in mice: Evaluation of 18F-FDG-PET and 18F-FLT-PET
E. Geven, S. Evers, T. Nayak, M. Bergström, F. Su, Danny Gerrits, G. Franssen, O. Boerman
Contrast Media and Molecular Imaging, 2015
Immuno-PET and immuno-SPECT of rheumatoid arthritis with radiolabeled anti-fibroblast activation protein antibody correlates with severity of arthritis
P. Laverman, T. van der Geest, S. Terry, Danny Gerrits, B. Walgreen, M. Helsen, T. Nayak, A. Freimoser-Grundschober, I. Waldhauer, R. Hosse, E. Moessner, P. Umaña, C. Klein, W. Oyen, M. Koenders, O. Boerman
Journal of Nuclear Medicine, 2015
Functional differences between neurotransmitter binding sites of muscle acetylcholine receptors
T. Nayak, Iva Bruhova, Srirupa Chakraborty, Shaweta Gupta, W. Zheng, A. Auerbach
Proceedings of the National Academy of Sciences of the United States of America, 2014
GPER-targeted, 99mTc-Labeled, nonsteroidal ligands demonstrate selective tumor imaging and in vivo estrogen binding
Tapan K. Nayak, Chinnasamy Ramesh, Helen J. Hathaway, Jeffrey P. Norenberg, Jeffrey B. Arterburn, Eric R. Prossnitz
Molecular Cancer Research, 2014
Spatial and temporal characteristics of normal and perturbed vesicle transport
G. Iacobucci, N. A. Rahman, A. A. Valtueña, T. Nayak, S. Gunawardena
Plos One, 2014
Preclinical evaluation of89Zr-labeled anti-CD44 monoclonal antibody RG7356 in mice and cynomolgus monkeys: Prelude to Phase 1 clinical studies
D. Vugts, D. Heuveling, M. Stigter-van Walsum, Stefan Weigand, Mats Bergstrom, G. V. van Dongen, T. Nayak
Mabs, 2014
Asymmetric transmitter binding sites of fetal muscle acetylcholine receptors shape their synaptic response
T. Nayak, A. Auerbach
Proceedings of the National Academy of Sciences of the United States of America, 2013
Orthotopic pleural mesothelioma in mice: SPECT/CT and MR imaging with HER1- and HER2-targeted radiolabeled antibodies
T. Nayak, M. Bernardo, D. Milenic, P. Choyke, M. Brechbiel
Radiology, 2013
PET imaging to monitor cancer therapy
G. Malviya, T. Nayak
Current Pharmaceutical Biotechnology, 2013
Synthesis and Characterization of Tricarbonyl-Re/Tc(I) Chelate Probes Targeting the G Protein-Coupled Estrogen Receptor GPER/GPR30
Ritwik Burai, C. Ramesh, T. Nayak, Megan K Dennis, B. Bryant, E. Prossnitz, J. B. Arterburn
Plos One, 2012
The intrinsic energy of the gating isomerization of a neuromuscular acetylcholine receptor channel
T. Nayak, P. Purohit, A. Auerbach
Journal of General Physiology, 2012
Effects of anti-VEGF on pharmacokinetics, biodistribution, and tumor penetration of trastuzumab in a preclinical breast cancer model
Cinthia V. Pastuskovas, Eduardo E. Mundo, Simon-Peter Williams, T. Nayak, Jason Ho, Sheila Ulufatu, S. Clark, S. Ross, Eric Cheng, Kathryn L Parsons-Reponte, G. Cain, M. van Hoy, Nicholas Majidy, S. Bheddah, Josefa dela Cruz Chuh, K. Kozak, N. Lewin-Koh, P. Nauka, D. Bumbaca, M. Sliwkowski, J. Tibbitts, F. Theil, P. Fielder, L. Khawli, C. Boswell
Molecular Cancer Therapeutics, 2012
PET and MRI of metastatic peritoneal and pulmonary colorectal cancer in mice with human epidermal growth factor receptor 1-targeted 89Zr- labeled panitumumab
T. Nayak, K. Garmestani, D. Milenic, M. Brechbiel
Journal of Nuclear Medicine, 2012
86Y based PET radiopharmaceuticals: Radiochemistry and biological applications
T. Nayak, M. Brechbiel
Medicinal Chemistry, 2011
HER1-targeted 86Y-panitumumab possesses superior targeting characteristics than 86Y-cetuximab for PET imaging of human malignant mesothelioma tumors xenografts
T. Nayak, K. Garmestani, D. Milenic, K. Baidoo, M. Brechbiel
Plos One, 2011
PET imaging of tumor angiogenesis in mice with VEGF-A-targeted 86Y-CHX-A‴-DTPA-bevacizumab
Tapan K. Nayak, Kayhan Garmestani, Kwamena E. Baidoo, Diane E. Milenic, Martin W. Brechbiel
International Journal of Cancer, 2011
In vitro and in vivo pre-clinical analysis of a F(ab')2 fragment of panitumumab for molecular imaging and therapy of HER1-positive cancers
Karen J Wong, Kwamena E Baidoo, Tapan K Nayak, Kayhan Garmestani, Martin W Brechbiel, Diane E Milenic
Ejnmmi Research, 2011
Targeting HER2: A report on the in vitro and in vivo pre-clinical data supporting trastuzumab as a radioimmunoconjugate for clinical trials
Diane E. Milenic, Karen J. Wong, Kwamena E. Baidoo, Tapan K. Nayak, Celeste A.S. Regino, Kayhan Garmestani, Martin W Brechbiel
Mabs, 2010
Influence of charge on cell permeability and tumor imaging of GPR30-targeted 111In-labeled nonsteroidal imaging agents
Tapan K. Nayak, Megan K. Dennis, Chinnasamy Ramesh, Ritwik Burai, Robert W. Atcher, Larry A. Sklar, Jeffrey P. Norenberg, Helen J. Hathaway, Jeffrey B. Arterburn, Eric R. Prossnitz
ACS Chemical Biology, 2010
Preparation, biological evaluation, and pharmacokinetics of the human anti-HER1 monoclonal antibody panitumumab labeled with 86Y for quantitative PET of carcinoma
Tapan K. Nayak, Kayhan Garmestani, Kwamena E. Baidoo, Diane E. Milenic, Martin W. Brechbiel
Journal of Nuclear Medicine, 2010
Synthesis and characterization of iodinated tetrahydroquinolines targeting the G protein-coupled estrogen receptor GPR30
Chinnasamy Ramesh, Tapan K. Nayak, Ritwik Burai, Megan K. Dennis, Helen J. Hathaway, Larry A. Sklar, Eric R. Prossnitz, Jeffrey B. Arterburn
Journal of Medicinal Chemistry, 2010
PET imaging of HER1-expressing xenografts in mice with 86Y-CHX- A″-DTPA-cetuximab
Tapan K. Nayak, Celeste A. S. Regino, Karen J. Wong, Diane E. Milenic, Kayhan Garmestani, Kwamena E. Baidoo, Lawrence P. Szajek, Martin W. Brechbiel
European Journal of Nuclear Medicine and Molecular Imaging, 2010
Radioimmunoimaging with longer-lived positron-emitting radionuclides: Potentials and challenges
Tapan K. Nayak, Martin W. Brechbiel
Bioconjugate Chemistry, 2009
In vivo effects of a GPR30 antagonist
Megan K Dennis, Ritwik Burai, Chinnasamy Ramesh, Whitney K Petrie, Sara N Alcon, Tapan K Nayak, Cristian G Bologa, Andrei Leitao, Eugen Brailoiu, Elena Deliu, Nae J Dun, Larry A Sklar, Helen J Hathaway, Jeffrey B Arterburn, Tudor I Oprea, Eric R Prossnitz
Nature Chemical Biology, 2009
Enhancement of somatostatin-receptor-targeted 177Lu-[DOTA0-Tyr3]-octreotide therapy by gemcitabine pretreatment-mediated receptor uptake, up-regulation and cell cycle modulation
Tapan K. Nayak, Robert W. Atcher, Eric R. Prossnitz, Jeffrey P. Norenberg
Nuclear Medicine and Biology, 2008
Preclinical development of a neutral, estrogen receptor-targeted, tridentate 99mTc(I)-estradiol-pyridin-2-yl hydrazine derivative for imaging of breast and endometrial cancers
Tapan K. Nayak, Helen J. Hathaway, Chinnasamy Ramesh, Jeffrey B. Arterburn, Donghai Dai, Larry A. Sklar, Jeffrey P. Norenberg, Eric R. Prossnitz
Journal of Nuclear Medicine, 2008
Somatostatin-receptor-targeted α-emitting 213Bi is therapeutically more effective than β--emitting 177Lu in human pancreatic adenocarcinoma cells
Tapan K. Nayak, Jeffrey P. Norenberg, Tamara L. Anderson, Eric R. Prossnitz, Michael G. Stabin, Robert W. Atcher
Nuclear Medicine and Biology, 2007
Linkage effects on binding affinity and activation of GPR30 and estrogen receptors ERα/β with tridentate pyridin-2-yl hydrazine tricarbonyl-Re/99mTc(I) chelates
Chinnasamy Ramesh, Bj Bryant, Tapan Nayak, Chetana M. Revankar, Tamara Anderson, Kathryn E. Carlson, John A. Katzenellenbogen, Larry A. Sklar, Jeffrey P. Norenberg, Eric R. Prossnitz, Jeffrey B. Arterburn
Journal of the American Chemical Society, 2006
213Bi-[DOTA0,Tyr3]octreotide peptide receptor radionuclide therapy of pancreatic tumors in a preclinical animal model
Jeffrey P. Norenberg, Boudewijn J. Krenning, Inge R.H.M. Konings, Donna F. Kusewitt, Tapan K. Nayak, Tamara L. Anderson, Marion de Jong, Kayhan Garmestani, Martin W. Brechbiel, Larry K. Kvols
Clinical Cancer Research, 2006
A comparison of high- versus low-linear energy transfer somatostatin receptor targeted radionuclide therapy in vitro
Tapan Nayak, Jeffrey Norenberg, Tamara Anderson, Robert Atcher
Cancer Biotherapy and Radiopharmaceuticals, 2005

Tapan Kumar Nayak

RESEARCH INTERESTS

Scopus Publications

RECENT SCHOLAR PUBLICATIONS

MOST CITED SCHOLAR PUBLICATIONS