Proposed ligand binding site of the transmembrane receptor for neurotensin(8-13)

被引:68
作者
Pang, YP
Cusack, B
Groshan, K
Richelson, E
机构
[1] Neurochemistry Research, Mayo Found. for Med. Educ./Research, Jacksonville
[2] Neuropsychopharmacology Research, Mayo Found. for Med. Educ./Research, Jacksonville
[3] Neurochemistry Research, Mayo Found. for Med. Educ./Research, Jacksonville, FL 32224
关键词
D O I
10.1074/jbc.271.25.15060
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We report here the first proposed ligand binding site of the transmembrane receptor for neurotensin (8-13) in human and rat, the corresponding bound conformation of the peptide ligand, and site directed mutagenesis studies that support the binding site model, These three-dimensional structures were generated by using a heuristic approach in conjunction with experimental data. The proposed neurotensin(8-13) binding site is primarily composed of eight residues (i.e., Phe(326), Ile(329), Trp(334), Phe(337), Tyr(339), Phe(341), Tyr(342), and Tyr(344) in the human receptor; Phe(331), Ile(334), Trp(339), Phe(342), Phe(344), Phe(346), Tyr(347), and Tyr(349) in the rat receptor) located in the third extracellular loop, The seven aromatic residues form an aromatic pocket on the extracellular surface of the neurotensin receptor to accommodate its ligands apparently by cation-pi, pi-pi, and hydrogen bonding interactions, The neurotensin(8-13) ligand adopts a compact conformation at the proposed binding site, In the bound conformation of neurotensin(8-13), the backbone of Arg(9)-Pro(10)-Tyr(11)-Ile(12) forms the proline type I turn, and the hydroxy group of Tyr(11) interacts with the two guanidinium groups of Arg(8) and Arg(9). These guanidinium groups are curled toward the hydroxy group so that they interact electrostatically with the hydroxy group, and that the guanidinium group of Arg(9) forms an intra-hydrogen bond with the hydroxy group. The proposed three-dimensional structure may not only provide a basis for rationalizing mutations of the neurotensin receptor gene but also offer insights into understanding the binding of many neurotensin analogs, biological functions of the neurotensin receptors, and structural elements for species specificity of the neurotensin receptors, and may expedite developing nonpeptidic neurotensin mimetics for the potential treatment of the neuropsychiatric diseases.
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页码:15060 / 15068
页数:9
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共 53 条
  • [1] Botto J. M., 1995, Society for Neuroscience Abstracts, V21, P1013
  • [2] AROMATIC-AROMATIC INTERACTION - A MECHANISM OF PROTEIN-STRUCTURE STABILIZATION
    BURLEY, SK
    PETSKO, GA
    [J]. SCIENCE, 1985, 229 (4708) : 23 - 28
  • [3] AMINO-AROMATIC INTERACTIONS IN PROTEINS
    BURLEY, SK
    PETSKO, GA
    [J]. FEBS LETTERS, 1986, 203 (02) : 139 - 143
  • [4] A 2ND GENERATION FORCE-FIELD FOR THE SIMULATION OF PROTEINS, NUCLEIC-ACIDS, AND ORGANIC-MOLECULES
    CORNELL, WD
    CIEPLAK, P
    BAYLY, CI
    GOULD, IR
    MERZ, KM
    FERGUSON, DM
    SPELLMEYER, DC
    FOX, T
    CALDWELL, JW
    KOLLMAN, PA
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1995, 117 (19) : 5179 - 5197
  • [5] DEVELOPMENTAL REGULATION OF NEUROTENSIN RECEPTOR EXPRESSION AND FUNCTION IN MURINE NEUROBLASTOMA CLONE N1E-115
    CUSACK, B
    STANTON, T
    RICHELSON, E
    [J]. EUROPEAN JOURNAL OF PHARMACOLOGY-MOLECULAR PHARMACOLOGY SECTION, 1991, 206 (04): : 339 - 342
  • [6] Chimeric rat/human neurotensin receptors localize a region of the receptor sensitive to binding of a novel, species-specific, picomolar affinity peptide
    Cusack, B
    Groshan, K
    McCormick, DJ
    Pang, YP
    Perry, R
    Phung, CT
    Souder, T
    Richelson, E
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (25) : 15054 - 15059
  • [7] CUSACK B, 1993, MOL PHARMACOL, V44, P1036
  • [8] A METHOD FOR RADIOLIGAND BINDING ASSAYS USING A ROBOTIC WORKSTATION
    CUSACK, B
    RICHELSON, E
    [J]. JOURNAL OF RECEPTOR RESEARCH, 1993, 13 (1-4): : 123 - 134
  • [9] PHARMACOLOGICAL AND BIOCHEMICAL PROFILES OF UNIQUE NEUROTENSIN-8-13 ANALOGS EXHIBITING SPECIES SELECTIVITY, STEREOSELECTIVITY, AND SUPERAGONISM
    CUSACK, B
    MCCORMICK, DJ
    PANG, YP
    SOUDER, T
    GARCIA, R
    FAUQ, A
    RICHELSON, E
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (31) : 18359 - 18366
  • [10] DEAKYNE CA, 1985, J AM CHEM SOC, V107, P474