Structural features of the inactive and active states of the melanin-concentrating hormone receptors: Insights from molecular simulations(538 views) Vitale RM, Pedone C, De Benedetti PG, Fanelli F
Department of Chemistry, Univ. of Modena and Reggio Emilia, Modena, Italy
Ist. di Biostrutture/Bioimmagini CNR, Napoli, Italy
Dulbecco Telethon Institute, Department of Chemistry, Univ. of Modena and Reggio Emilia, Modena, Italy
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Boutin, J. A., Suply, T., Audinot, V., Rodriguez, M., Beauverger, P., Nicolas, J. -P., Galizzi, J. -P., Fauchere, J. -L., Melanin-concentrating hormone and its receptors: State of the art (2002) Can J Physiol Pharmacol, 80, pp. 388-395. , and references therein
Qu, D., Ludwig, D. S., Gammeltoft, S., Piper, M., Pelleymounter, M. A., Cullen, M. J., Mathes, W. F., Maratos-Flier, E., A role for melanin-concentrating hormone in the central regulation of feeding behaviour (1996) Nature, 380, pp. 243-247
Sailer, A. W., Sano, H., Zeng, Z., McDonald, T. P., Pan, J., Pong, S. S., Feighner, S. D., Liu, Q., Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R (2001) Proc Natl Acad Sci USA, 98, pp. 7564-7569
Bednarek, M. A., Feighner, S. D., Hreniuk, D. L., Palyha, O. C., Morin, N. R., Sadowski, S. J., MacNeil, D. J., Van Der Ploeg, L. H. J., Short segment of human melanin-concentrating hormone that is sufficient for full activation of human melanin-concentrating hormone receptors 1 and 2 (2001) Biochemistry, 40, pp. 9379-9386
Brown, D. W., Campbell, M. M., Kinsman, R. G., White, P. D., Moss, C. A., Osguthorpe, D. J., Paul, P. K., Baker, B. I., Melanin-concentrating hormone: A structural and conformational study based on synthesis, biological activity, high-field NMR, and molecular modeling techniques (1990) Biopolymers, 29, pp. 609-622
Paul, P. K. C., Dauber-Osguthorpe, P., Campbell, M. M., Brown, D. W., Kinsman, R. G., Moss, C., Osguthorpe, D. J., Accessible conformations of melanin-concentrating hormone: A molecular dynamics approach (1990) Biopolymers, 29, pp. 623-637
Vitale, R. M., Zaccaro, L., Di Blasio, B., Fattorusso, R., Isernia, C., Amodeo, P., Pedone, C., Saviano, M., Conformational features of human melanin-concentrating hormone: A NMR and computational analysis (2003) ChemBioChem, 4, pp. 73-81
Teller, D. C., Okada, T., Behnke, C. A., Palczewski, C., Advances in determination of a high resolution three dimensional structure of rhodopsin, a model of G protein coupled receptors (GPCRs) (2001) Biochemistry, 40, pp. 7761-7772
Greasley, P. J., Fanelli, F., Scheer, A., Abuin, L., Nenniger-Tosato, M., De Benedetti, P. G., Cotecchia, S., Mutational and computational analysis of the 1b- adrenergic receptor: Involvement of basic and hydrophobic residues in receptor activation and G protein coupling (2001) J Biol Chem, 276, pp. 6485-6494
Brooks, B. R., Bruccoleri, R. E., Olafson, B. D., States, D. J., Swaminathan, S., Karplus, M., CHARMML: A program for macromolecular energy, minimization and dynamics calculations (1983) J Comput Chem, 4, pp. 187-217
MacKerell Jr., A. D., Bashford, D., Bellott, M., Dunbrack Jr., R. L., Evanseck, J. D., Field, M. J., Fischer, S., Karplus, M., All-atom empirical potential for molecular modeling and dynamics studies of proteins (1998) J Phys Chem B, 102, pp. 3586-3616
Ballesteros, J. A., Weinstein, H., Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors (1995) Methods Neurosci, 25, pp. 366-428
Farrens, D. L., Altenbach, C., Yang, K., Hubbell, W. L., Khorana, H. G., Requirement of rigid-body motion of transmembrane helices for light activation of rhodopsin (1996) Science, 274, pp. 768-770
Dewar, M. J. S., Zoebisch, E. G., Healey, E. F., Stewart, J. J. P., AM1: A new general purpose quantum mechanical molecular model (1985) J Am Chem Soc, 107, pp. 3902-3909
Shapiro, D. A., Kristiansen, K., Weiner, D. M., Kroeze, W. K., Roth, B. L. J., Evidence for a model of agonist induced activation of 5-hydroxytryptamine 2A serotonin receptors that involves the disruption of a strong ionic interaction between helices 3 and 6 (2002) J Biol Chem, 277, pp. 11441-11449
Elling, C. E., Thirstrup, K., Holst, B., Schwartz, T. W., Conversion of agonist site to metal-ion chelator site in the 2-adrenergic receptor (1999) Proc Natl Acad Sci USA, 96, pp. 12322-12327
Javitch, J. A., Ballesteros, J. A., Weinstein, H., Chen, J., A cluster of aromatic residues in the sixth membrane-spanning segment of the dopamine D2 receptor is accessible in the binding-site crevice (1998) Biochemistry, 37, pp. 998-1006
Meng, E. C., Bourne, H., Receptor activation: What does rhodopsin structure tell us? (2001) Trends Pharmacol Sci, 22, pp. 587-593. , and references therein
Sansom, M. S. P., Weinstein, H., Hinges, swilves and switches: The role of prolines in signalling via transmembrane -helices (2000) Trends Pharm Sci, 21, pp. 445-451. , and references therein
Schutz, C. N., Warshel, A., What are the dielectric "constants" of proteins and how to validate electrostatic models? (2001) Proteins, 44, pp. 400-417. , and references therein
Structural features of the inactive and active states of the melanin-concentrating hormone receptors: Insights from molecular simulations
Comparative molecular dynamics simulations of both subtypes 1 and 2 of the melanin-concentrating hormone receptor (MCHR1 and MCHR2, respectively) in their free and hormone-bound forms have been carried out. The hormone has been used in its full-length and truncated forms, as well as in 16 mutated forms. Moreover, MCHR1 has been simulated in complex with T-226296, a novel orally active and selective antagonist. The comparative analysis of an extended number of receptor configurations suggests that the differences between inactive (i.e., free and antagonist-bound) and active (i.e., agonist-bound) states of MCHRs involve the receptor portions close to the E/DRY and NPxxY motifs, with prominence to the cytosolic extensions of helices 2, 3, 6, and 7. In fact, the active forms of these receptors share the release of selected intramolecular interactions found in the inactive forms, such as that between R3.50 of the E/DRY motif and D2.40, and that between Y7.53 of the NPxxY motif and F7.60. Another feature of the active forms of both MCHRs is the approach of "helix 8" to the cytosolic extension of helix 3. These features of the active forms are concurrent with the opening of a cleft at the cytosolic end of the helix bundle. For both MCHRs, the agonist-induced chemical information transfer from the extracellular to the cytosolic domains is mediated by a cluster of aromatic amino acids in helix 6, following the ligand interaction with selected amino acids in the extracellular half of the receptor. (C) 2004 Wiley-Liss, Inc.
Structural features of the inactive and active states of the melanin-concentrating hormone receptors: Insights from molecular simulations
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Structural features of the inactive and active states of the melanin-concentrating hormone receptors: Insights from molecular simulations