Evan N. Feinberg
Stanford University
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Featured researches published by Evan N. Feinberg.
Nature | 2015
Weijiao Huang; Aashish Manglik; A. J. Venkatakrishnan; Toon Laeremans; Evan N. Feinberg; Adrian L. Sanborn; Hideaki E. Kato; Kathryn E. Livingston; Thor S. Thorsen; Ralf C. Kling; Sébastien Granier; Peter Gmeiner; Stephen M. Husbands; John R. Traynor; William I. Weis; Jan Steyaert; Ron O. Dror; Brian K. Kobilka
Activation of the μ-opioid receptor (μOR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for μOR activation, here we report a 2.1 Å X-ray crystal structure of the murine μOR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the μOR binding pocket are subtle and differ from those observed for agonist-bound structures of the β2-adrenergic receptor (β2AR) and the M2 muscarinic receptor. Comparison with active β2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the μOR, and molecular dynamics simulations illustrate how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three G-protein-coupled receptors.
Science | 2015
John S. Burg; Jessica R. Ingram; A. J. Venkatakrishnan; Kevin M. Jude; Abhiram Dukkipati; Evan N. Feinberg; Alessandro Angelini; Deepa Waghray; Ron O. Dror; Hidde L. Ploegh; K. Christopher Garcia
Molecular “go” signals reveal their secrets Chemokines are proteins that direct how cells move within the body. For instance, chemokines help immune cells locate invading pathogens and ensure that cells position themselves correctly within a developing organ. Cells detect chemokines through G protein–coupled receptors on their surface; however, the molecular details of how these proteins interact remain unclear (see the Perspective by Standfuss). Qin et al. solved the crystal structure of the chemokine receptor CXCR4 bound to the viral chemokine vMIP-II. Burg et al. solved the crystal structure of a viral chemokine receptor bound to the chemokine domain of CX3CL1. Given the role of chemokines in a number of diseases, these results may help in future drug design. Science, this issue p. 1117, p. 1113; see also p. 1071 The crystal structure of a viral chemokine receptor bound to the chemokine CX3CL1 provides insights into chemokine recognition. [Also see Perspective by Standfuss] Chemokines are small proteins that function as immune modulators through activation of chemokine G protein–coupled receptors (GPCRs). Several viruses also encode chemokines and chemokine receptors to subvert the host immune response. How protein ligands activate GPCRs remains unknown. We report the crystal structure at 2.9 angstrom resolution of the human cytomegalovirus GPCR US28 in complex with the chemokine domain of human CX3CL1 (fractalkine). The globular body of CX3CL1 is perched on top of the US28 extracellular vestibule, whereas its amino terminus projects into the central core of US28. The transmembrane helices of US28 adopt an active-state–like conformation. Atomic-level simulations suggest that the agonist-independent activity of US28 may be due to an amino acid network evolved in the viral GPCR to destabilize the receptor’s inactive state.
International Journal of Nanomedicine | 2014
J. Justin Mulvey; Evan N. Feinberg; Simone Alidori; Michael R. McDevitt; Daniel A. Heller; David A. Scheinberg
We aimed to create a more robust and more accessible standard for amine-modifying single-walled carbon nanotubes (SWCNTs). A 1,3-cycloaddition was developed using an azomethine ylide, generated by reacting paraformaldehyde and a side-chain-Boc (tert-Butyloxycarbonyl)-protected, lysine-derived alpha-amino acid, H-Lys(Boc)-OH, with purified SWCNT or C60. This cycloaddition and its lysine adduct provides the benefits of dense, covalent modification, ease of purification, commercial availability of reagents, and pH-dependent solubility of the product. Subsequently, SWCNTs functionalized with lysine amine handles were covalently conjugated to a radiometalated chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The 111In-labeled construct showed rapid renal clearance in a murine model and a favorable biodistribution, permitting utility in biomedical applications. Functionalized SWCNTs strongly wrapped small interfering RNA (siRNA). In the first disclosed deployment of thermophoresis with carbon nanotubes, the lysine-modified tubes showed a desirable, weak SWCNT-albumin binding constant. Thus, lysine-modified nanotubes are a favorable candidate for medicinal work.
PLOS ONE | 2017
Bitna Yi; Alam Jahangir; Andrew K. Evans; Denise Isabelle Briggs; Kristine Ravina; Jacqueline Ernest; Amir Barati Farimani; Wenchao Sun; Jayakumar Rajadas; Michael R. Green; Evan N. Feinberg; Vijay S. Pande; Mehrdad Shamloo
The beta-1 adrenergic receptor (ADRB1) is a promising therapeutic target intrinsically involved in the cognitive deficits and pathological features associated with Alzheimer’s disease (AD). Evidence indicates that ADRB1 plays an important role in regulating neuroinflammatory processes, and activation of ADRB1 may produce neuroprotective effects in neuroinflammatory diseases. Novel small molecule modulators of ADRB1, engineered to be highly brain permeable and functionally selective for the G protein with partial agonistic activity, could have tremendous value both as pharmacological tools and potential lead molecules for further preclinical development. The present study describes our ongoing efforts toward the discovery of functionally selective partial agonists of ADRB1 that have potential therapeutic value for AD and neuroinflammatory disorders, which has led to the identification of the molecule STD-101-D1. As a functionally selective agonist of ADRB1, STD-101-D1 produces partial agonistic activity on G protein signaling with an EC50 value in the low nanomolar range, but engages very little beta-arrestin recruitment compared to the unbiased agonist isoproterenol. STD-101-D1 also inhibits the tumor necrosis factor α (TNFα) response induced by lipopolysaccharide (LPS) both in vitro and in vivo, and shows high brain penetration. Other than the therapeutic role, this newly identified, functionally selective, partial agonist of ADRB1 is an invaluable research tool to study mechanisms of G protein-coupled receptor signal transduction.
Biophysical Journal | 2018
Amir Barati Farimani; Evan N. Feinberg; Vijay S. Pande
Many important analgesics relieve pain by binding to the
Chemical Science | 2018
Zhenqin Wu; Bharath Ramsundar; Evan N. Feinberg; Joseph Gomes; Caleb Geniesse; Aneesh S. Pappu; Karl Leswing; Vijay S. Pande
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arXiv: Learning | 2017
Joseph Gomes; Bharath Ramsundar; Evan N. Feinberg; Vijay S. Pande
-Opioid Receptor (
Archive | 2014
Evan N. Feinberg; Julien Clancy
\mu
arXiv: Learning | 2018
Evan N. Feinberg; Debnil Sur; Zhenqin Wu; Brooke E. Husic; Huanghao Mai; Yang Li; Saisai Sun; Jianyi Yang; Bharath Ramsundar; Vijay S. Pande
OR), which makes the
arXiv: Learning | 2018
Evan N. Feinberg; Debnil Sur; Brooke E. Husic; Doris Mai; Yang Li; Jianyi Yang; Bharath Ramsundar; Vijay S. Pande
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