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Interactions of the melanocortin-4 receptor with the peptide agonist NDP-MSH.

Chapman KL, Kinsella GK, Cox A, Donnelly D, Findlay JB - J. Mol. Biol. (2010)

Bottom Line: For the first time, the interactions between the terminal regions of NDP-MSH and the receptor are described.The amino-terminus appears to be adjacent to a series of hydrophilic residues with novel interactions at Cys196 (TM5) and Asp189 (extracellular loop 2).These interactions are reminiscent of sequential ligand binding exhibited by the beta(2)-adrenergic receptor, with the former interaction being equivalent to the known interaction involving Ser204 of the beta(2)-adrenergic receptor.

View Article: PubMed Central - PubMed

Affiliation: School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.

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(a) Three-dimensional image of the R⁎ hMC4R model. GαCT(340–350)K341L) is indicated in purple. (b) Three-dimensional image zoomed to the area of the E/DRY motif, with interacting residues indicated. The outer helices were removed for clarity. (c) Three-dimensional image zoomed to the area of the NPxxY motif (in yellow); Asp146 and Arg147 are indicated in blue, with interacting residues identified (see the text for further details).The images were generated using PyMOL.54
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fig1: (a) Three-dimensional image of the R⁎ hMC4R model. GαCT(340–350)K341L) is indicated in purple. (b) Three-dimensional image zoomed to the area of the E/DRY motif, with interacting residues indicated. The outer helices were removed for clarity. (c) Three-dimensional image zoomed to the area of the NPxxY motif (in yellow); Asp146 and Arg147 are indicated in blue, with interacting residues identified (see the text for further details).The images were generated using PyMOL.54

Mentions: An outline of the developed MC4R model showing the seven TM regions and the two proline kinks present at Pro260 (TM6) and Pro299 (TM7) is presented in Fig. 1. The N-terminus, C-terminus, and loops were modeled from the opsin template with subsequent loop refinement. Notably, the highly conserved ECL1 of the MCRs, containing the acidic Asp-x-Asp motif, interacts with the N-terminus and TM2. MCRs lack the characteristic long ECL2 loop of class A GPCRs at the entrance of the ligand binding pocket, which may allow greater access to the binding pocket.54 In the opsin crystal structure (PDB code 3DQB), GαCT(340–350)K341L binds to an intracellular site opened by an outward tilt of TM6, a pairing of TM5 and TM6, and a restructured TM7–helix 8 kink.51 A number of interactions with TM3, TM5, and TM6 of MC4R involving GαCT and our developed MC4R model were observed. First, His222 at the end of TM5 comes into contact with Ile340 and Glu342 of GαCT. From TM3, Thr150 and Arg147 of the conserved DRY motif form hydrogen bonds with Lys345 and Asp346 of GαCT, respectively, while Lys242 of TM6 hydrogen bonds with Phe350 of GαCT.


Interactions of the melanocortin-4 receptor with the peptide agonist NDP-MSH.

Chapman KL, Kinsella GK, Cox A, Donnelly D, Findlay JB - J. Mol. Biol. (2010)

(a) Three-dimensional image of the R⁎ hMC4R model. GαCT(340–350)K341L) is indicated in purple. (b) Three-dimensional image zoomed to the area of the E/DRY motif, with interacting residues indicated. The outer helices were removed for clarity. (c) Three-dimensional image zoomed to the area of the NPxxY motif (in yellow); Asp146 and Arg147 are indicated in blue, with interacting residues identified (see the text for further details).The images were generated using PyMOL.54
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3101337&req=5

fig1: (a) Three-dimensional image of the R⁎ hMC4R model. GαCT(340–350)K341L) is indicated in purple. (b) Three-dimensional image zoomed to the area of the E/DRY motif, with interacting residues indicated. The outer helices were removed for clarity. (c) Three-dimensional image zoomed to the area of the NPxxY motif (in yellow); Asp146 and Arg147 are indicated in blue, with interacting residues identified (see the text for further details).The images were generated using PyMOL.54
Mentions: An outline of the developed MC4R model showing the seven TM regions and the two proline kinks present at Pro260 (TM6) and Pro299 (TM7) is presented in Fig. 1. The N-terminus, C-terminus, and loops were modeled from the opsin template with subsequent loop refinement. Notably, the highly conserved ECL1 of the MCRs, containing the acidic Asp-x-Asp motif, interacts with the N-terminus and TM2. MCRs lack the characteristic long ECL2 loop of class A GPCRs at the entrance of the ligand binding pocket, which may allow greater access to the binding pocket.54 In the opsin crystal structure (PDB code 3DQB), GαCT(340–350)K341L binds to an intracellular site opened by an outward tilt of TM6, a pairing of TM5 and TM6, and a restructured TM7–helix 8 kink.51 A number of interactions with TM3, TM5, and TM6 of MC4R involving GαCT and our developed MC4R model were observed. First, His222 at the end of TM5 comes into contact with Ile340 and Glu342 of GαCT. From TM3, Thr150 and Arg147 of the conserved DRY motif form hydrogen bonds with Lys345 and Asp346 of GαCT, respectively, while Lys242 of TM6 hydrogen bonds with Phe350 of GαCT.

Bottom Line: For the first time, the interactions between the terminal regions of NDP-MSH and the receptor are described.The amino-terminus appears to be adjacent to a series of hydrophilic residues with novel interactions at Cys196 (TM5) and Asp189 (extracellular loop 2).These interactions are reminiscent of sequential ligand binding exhibited by the beta(2)-adrenergic receptor, with the former interaction being equivalent to the known interaction involving Ser204 of the beta(2)-adrenergic receptor.

View Article: PubMed Central - PubMed

Affiliation: School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.

Show MeSH