Diseño de péptidos inhibidores de interacciones de la subunidad GluN2B del receptor NMDA en isquemia
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Resumen
El receptor NMDA constituye el principal subtipo de receptores de glutamato implicados en procesos fisiológicos tales como desarrollo neuronal, plasticidad sináptica, memoria y aprendizaje y numerosas condiciones patológicas como daño isquémico, dolor crónico, psicosis, y otros trastornos degenerativos. Se ha sugerido la regulación por fosforilación como un mecanismo de alteración de la permeabilidad relativa del NMDAR a Ca2+ durante la isquemia. En este trabajo se diseñó una serie de péptidos basados en interacciones de la subunidad GluN2B con las proteínas DAPK1, SRC y D2R, relacionadas con los efectos generados tras un evento isquémico. La identificación de sitios de unión entre estas moléculas y GluN2B permitió hacer un diseño in silico de péptidos que eventualmente pueden bloquear dichas interacciones y reducir los efectos nocivos de patologías como la isquemia. Nuestros resultados demuestran que el diseño racional de péptidos es una buena estrategia para la generación de nuevos agentes terapéuticos.
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Citri, A and Malenka, RC. Synaptic plasticity: multiple forms, functions, and mechanisms. 33 (1): p. 18-41. 2008
Hardingham, GE and Bading, H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. 11 (10): p. 682-696. 2010
Mony, L, Kew, JN, Gunthorpe, MJ and Paoletti, P. Allosteric modulators of NR2B‐containing NMDA receptors: molecular mechanisms and therapeutic potential. 157 (8): p. 1301-1317. 2009
Traynelis, SF, Wollmuth, LP, McBain, CJ, Menniti, FS, Vance, KM, Ogden, KK, Hansen, KB, Yuan, H, Myers, SJ and Dingledine, R. Glutamate receptor ion channels: structure, regulation, and function. 62 (3): p. 405-496. 2010
Madden, DR. The structure and function of glutamate receptor ion channels. 3 (2): p. 91-101. 2002
Akazawa, C, Shigemoto, R, Bessho, Y, Nakanishi, S and Mizuno, N. Differential expression of five N‐methyl‐D‐aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats. 347 (1): p. 150-160. 1994
Monyer, H, Burnashev, N, Laurie, DJ, Sakmann, B and Seeburg, PH. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. 12 (3): p. 529-540. 1994
Sobolevsky, AI, Rosconi, MP and Gouaux, E. X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. 462 (7274): p. 745-756. 2009
Ataman, ZA, Gakhar, L, Sorensen, BR, Hell, JW and Shea, MA. The NMDA receptor NR1 C1 region bound to calmodulin: structural insights into functional differences between homologous domains. 15 (12): p. 1603-1617. 2007
Aarts, MM and Tymianski, M. Molecular mechanisms underlying specificity of excitotoxic signaling in neurons. 4 (2): p. 137-147. 2004
Green, AR. Why do neuroprotective drugs that are so promising in animals fail in the clinic? An industry perspective. 29 (11): p. 1030-1034. 2002
Parsons, CG, Danysz, W and Lodge, D. Introduction to glutamate receptors, their function and pharmacology. p. 1-30. 2002
Lo, EH, Dalkara, T and Moskowitz, MA. Mechanisms, challenges and opportunities in stroke. 4 (5): p. 399-414. 2003
Hoyte, L, Barber, P, Buchan, A and Hill, M. The rise and fall of NMDA antagonists for ischemic stroke. 4 (2): p. 131-136. 2004
Small, DL and Tauskela, JS. Glutamate receptor pharmacology: Lessons learned from the last decade of stroke trials. p. 27-45. 2005
Wang, CX and Shuaib, A. NMDA/NR2B selective antagonists in the treatment of ischemic brain injury. 4 (2): p. 143-151. 2005
Muir, KW. Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists. 6 (1): p. 53-60. 2006
Sacco, RL, DeRosa, JT, Haley Jr, EC, Levin, B, Ordronneau, P, Phillips, SJ, Rundek, T, Snipes, RG, Thompson, JL and Investigators, GA. Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. 285 (13): p. 1719-1728. 2001
Yurkewicz, L, Weaver, J, Bullock, MR and Marshall, LF. The effect of the selective NMDA receptor antagonist traxoprodil in the treatment of traumatic brain injury. 22 (12): p. 1428-1443. 2005
Kotermanski, SE and Johnson, JW. Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer's drug memantine. 29 (9): p. 2774-2779. 2009
Tu, W, Xu, X, Peng, L, Zhong, X, Zhang, W, Soundarapandian, MM, Belal, C, Wang, M, Jia, N and Zhang, W. DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke. 140 (2): p. 222-234. 2010
Guo, W, Zou, S, Guan, Y, Ikeda, T, Tal, M, Dubner, R and Ren, K. Tyrosine phosphorylation of the NR2B subunit of the NMDA receptor in the spinal cord during the development and maintenance of inflammatory hyperalgesia. 22 (14): p. 6208-6217. 2002
Sinai, L, Duffy, S and Roder, JC. Src inhibition reduces NR2B surface expression and synaptic plasticity in the amygdala. 17 (8): p. 364-371. 2010
Liu, X-Y, Chu, X-P, Mao, L-M, Wang, M, Lan, H-X, Li, M-H, Zhang, G-C, Parelkar, NK, Fibuch, EE and Haines, M. Modulation of D2R-NR2B interactions in response to cocaine. 52 (5): p. 897-909. 2006
Hall, R and Soderling, T. Quantitation of AMPA receptor surface expression in cultured hippocampal neurons. 78 (2): p. 361-371. 1997
Liu, S-b and Zhao, M-g. Neuroprotective effect of estrogen: role of nonsynaptic NR2B-containing NMDA receptors. 93 p. 27-31. 2013
Sun, Y, Zhang, L, Chen, Y, Zhan, L and Gao, Z. Therapeutic Targets for Cerebral Ischemia Based on the Signaling Pathways of the GluN2B C Terminus. 46 (8): p. 2347-2353. 2015
Jensen, LJ, Kuhn, M, Stark, M, Chaffron, S, Creevey, C, Muller, J, Doerks, T, Julien, P, Roth, A and Simonovic, M. STRING 8—a global view on proteins and their functional interactions in 630 organisms. 37 (suppl 1): p. D412-D416. 2009
Goujon, M, McWilliam, H, Li, W, Valentin, F, Squizzato, S, Paern, J and Lopez, R. A new bioinformatics analysis tools framework at EMBL–EBI. 38 (suppl 2): p. W695-W699. 2010
Berman, HM, Bhat, TN, Bourne, PE, Feng, Z, Gilliland, G, Weissig, H and Westbrook, J. The Protein Data Bank and the challenge of structural genomics. 7 p. 957-959. 2000
Zhang, Y. I-TASSER server for protein 3D structure prediction. 9 (1): p. 40. 2008
Laskowski, RA, Hutchinson, EG, Michie, AD, Wallace, AC, Jones, ML and Thornton, JM. PDBsum: a Web-based database of summaries and analyses of all PDB structures. 22 (12): p. 488-490. 1997
Tereshko, V, Teplova, M, Brunzelle, J, Watterson, DM and Egli, M. Crystal structures of the catalytic domain of human protein kinase associated with apoptosis and tumor suppression. 8 (10): p. 899-907. 2001
Pettersen, EF, Goddard, TD, Huang, CC, Couch, GS, Greenblatt, DM, Meng, EC and Ferrin, TE. UCSF Chimera—a visualization system for exploratory research and analysis. 25 (13): p. 1605-1612. 2004
Trott, O and Olson, AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. 31 (2): p. 455-461. 2010
London, N, Raveh, B, Cohen, E, Fathi, G and Schueler-Furman, O. Rosetta FlexPepDock web server—high resolution modeling of peptide–protein interactions. 39 (suppl 2): p. W249-W253. 2011
Raveh, B, London, N and Schueler‐Furman, O. Sub‐angstrom modeling of complexes between flexible peptides and globular proteins. 78 (9): p. 2029-2040. 2010
Husi, H, Ward, MA, Choudhary, JS, Blackstock, WP and Grant, SG. Proteomic analysis of NMDA receptor–adhesion protein signaling complexes. 3 (7): p. 661-669. 2000
Choi, UB, Xiao, S, Wollmuth, LP and Bowen, ME. Effect of Src kinase phosphorylation on disordered C-terminal domain of N-methyl-D-aspartic acid (NMDA) receptor subunit GluN2B protein. 286 (34): p. 29904-29912. 2011
Hennequin, LF, Allen, J, Breed, J, Curwen, J, Fennell, M, Green, TP, Lambert-van der Brempt, C, Morgentin, R, Norman, RA and Olivier, A. N-(5-chloro-1, 3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl) ethoxy]-5-(tetrahydro-2 h-pyran-4-yloxy) quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. 49 (22): p. 6465-6488. 2006
Morris, AL, MacArthur, MW, Hutchinson, EG and Thornton, JM. Stereochemical quality of protein structure coordinates. 12 (4): p. 345-364. 1992
Kyte, J and Doolittle, RF. A simple method for displaying the hydropathic character of a protein. 157 (1): p. 105-132. 1982
Lin, Y-Z, Yao, S, Veach, RA, Torgerson, TR and Hawiger, J. Inhibition of nuclear translocation of transcription factor NF-κB by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence. 270 (24): p. 14255-14258. 1995
Embury, J, Klein, D, Pileggi, A, Ribeiro, M, Jayaraman, S, Molano, RD, Fraker, C, Kenyon, N, Ricordi, C and Inverardi, L. Proteins linked to a protein transduction domain efficiently transduce pancreatic islets. 50 (8): p. 1706-1713. 2001
Johnson, JL, Lowell, BC, Ryabinina, OP, Lloyd, RS and McCullough, AK. TAT-mediated delivery of a DNA repair enzyme to skin cells rapidly initiates repair of UV-induced DNA damage. 131 (3): p. 753-761. 2011