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Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling.

Leander M, Bass C, Marchetti K, Maynard BF, Wulff JP, Ons S, Nichols R - PLoS ONE (2015)

Bottom Line: RhpMS and DrmMS decreased R. prolixus cardiac contractility dose dependently with EC50 values of 140 nM and 50 nM.Based on ligand-receptor contacts, we designed RhpMS analogs believed to be an active core and antagonist; testing on heart confirmed these predictions.The active core docking mimicked RhpMS, however, the antagonist did not.

View Article: PubMed Central - PubMed

Affiliation: Undergraduate Biochemistry Program, Chemistry Department, University of Michigan, Ann Arbor, Michigan, United States of America, 48109; Biological Chemistry Department, University of Michigan Medical School, Ann Arbor, Michigan, United States of America, 48109.

ABSTRACT
Peptidergic signaling regulates cardiac contractility; thus, identifying molecular switches, ligand-receptor contacts, and antagonists aids in exploring the underlying mechanisms to influence health. Myosuppressin (MS), a decapeptide, diminishes cardiac contractility and gut motility. Myosuppressin binds to G protein-coupled receptor (GPCR) proteins. Two Drosophila melanogaster myosuppressin receptors (DrmMS-Rs) exist; however, no mechanism underlying MS-R activation is reported. We predicted DrmMS-Rs contained molecular switches that resembled those of Rhodopsin. Additionally, we believed DrmMS-DrmMS-R1 and DrmMS-DrmMS-R2 interactions would reflect our structure-activity relationship (SAR) data. We hypothesized agonist- and antagonist-receptor contacts would differ from one another depending on activity. Lastly, we expected our study to apply to other species; we tested this hypothesis in Rhodnius prolixus, the Chagas disease vector. Searching DrmMS-Rs for molecular switches led to the discovery of a unique ionic lock and a novel 3-6 lock, as well as transmission and tyrosine toggle switches. The DrmMS-DrmMS-R1 and DrmMS-DrmMS-R2 contacts suggested tissue-specific signaling existed, which was in line with our SAR data. We identified R. prolixus (Rhp)MS-R and discovered it, too, contained the unique myosuppressin ionic lock and novel 3-6 lock found in DrmMS-Rs as well as transmission and tyrosine toggle switches. Further, these motifs were present in red flour beetle, common water flea, honey bee, domestic silkworm, and termite MS-Rs. RhpMS and DrmMS decreased R. prolixus cardiac contractility dose dependently with EC50 values of 140 nM and 50 nM. Based on ligand-receptor contacts, we designed RhpMS analogs believed to be an active core and antagonist; testing on heart confirmed these predictions. The active core docking mimicked RhpMS, however, the antagonist did not. Together, these data were consistent with the unique ionic lock, novel 3-6 lock, transmission switch, and tyrosine toggle switch being involved in mechanisms underlying TM movement and MS-R activation, and the ability of MS agonists and antagonists to influence physiology.

No MeSH data available.


Related in: MedlinePlus

DrmMS-Rs molecular switches.DrmMS-Rs contained a unique ionic lock and novel 3–6 lock that stabilized the inactive state of the receptor. Residues involved in the ionic lock (top left), 3–6 lock (top right), transmission switch (bottom left), and tyrosine toggle switch (bottom right) are shown for DrmMS-R1 (blue) and DrmMS-R2 (gold). The receptors are shown as ribbons with TM1–7 labeled.
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pone.0120492.g001: DrmMS-Rs molecular switches.DrmMS-Rs contained a unique ionic lock and novel 3–6 lock that stabilized the inactive state of the receptor. Residues involved in the ionic lock (top left), 3–6 lock (top right), transmission switch (bottom left), and tyrosine toggle switch (bottom right) are shown for DrmMS-R1 (blue) and DrmMS-R2 (gold). The receptors are shown as ribbons with TM1–7 labeled.

Mentions: To begin our studies, we predicted DrmMS-Rs contained molecular switches that resembled those of Rhodopsin. DrmMS-Rs are classified as members of the Rhodopsin family A receptors [6]; as such, we expected them to contain an ionic lock, 3–7 lock, transmission switch, and tyrosine toggle switch [1]. No MS-R molecular switch was previously reported in the literature. The DrmMS-R structures contained structural motifs reminiscent of those present in Rhodopsin. The ionic lock switch was represented by the WRY motif on TM3 [Fig. 1]. It was present in the DrmMS-Rs in the same location as ERY in Rhodopsin (PDB ID: 1F88) [20]. The WRY motif of DrmMS-R interacted with multiple T residues on TM6. Even so, DrmMS-R lost an electrostatic interaction between TM3 and TM6 due to the absence of a negatively-charged residue on TM6 within the range of a salt bridge. Also, because WRY did not contain E it could not form an intra-motif interaction with R130/125 (notation used to indicate R130 in DrmMS-R1 and R125 in DrmMS-R2).


Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling.

Leander M, Bass C, Marchetti K, Maynard BF, Wulff JP, Ons S, Nichols R - PLoS ONE (2015)

DrmMS-Rs molecular switches.DrmMS-Rs contained a unique ionic lock and novel 3–6 lock that stabilized the inactive state of the receptor. Residues involved in the ionic lock (top left), 3–6 lock (top right), transmission switch (bottom left), and tyrosine toggle switch (bottom right) are shown for DrmMS-R1 (blue) and DrmMS-R2 (gold). The receptors are shown as ribbons with TM1–7 labeled.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4368603&req=5

pone.0120492.g001: DrmMS-Rs molecular switches.DrmMS-Rs contained a unique ionic lock and novel 3–6 lock that stabilized the inactive state of the receptor. Residues involved in the ionic lock (top left), 3–6 lock (top right), transmission switch (bottom left), and tyrosine toggle switch (bottom right) are shown for DrmMS-R1 (blue) and DrmMS-R2 (gold). The receptors are shown as ribbons with TM1–7 labeled.
Mentions: To begin our studies, we predicted DrmMS-Rs contained molecular switches that resembled those of Rhodopsin. DrmMS-Rs are classified as members of the Rhodopsin family A receptors [6]; as such, we expected them to contain an ionic lock, 3–7 lock, transmission switch, and tyrosine toggle switch [1]. No MS-R molecular switch was previously reported in the literature. The DrmMS-R structures contained structural motifs reminiscent of those present in Rhodopsin. The ionic lock switch was represented by the WRY motif on TM3 [Fig. 1]. It was present in the DrmMS-Rs in the same location as ERY in Rhodopsin (PDB ID: 1F88) [20]. The WRY motif of DrmMS-R interacted with multiple T residues on TM6. Even so, DrmMS-R lost an electrostatic interaction between TM3 and TM6 due to the absence of a negatively-charged residue on TM6 within the range of a salt bridge. Also, because WRY did not contain E it could not form an intra-motif interaction with R130/125 (notation used to indicate R130 in DrmMS-R1 and R125 in DrmMS-R2).

Bottom Line: RhpMS and DrmMS decreased R. prolixus cardiac contractility dose dependently with EC50 values of 140 nM and 50 nM.Based on ligand-receptor contacts, we designed RhpMS analogs believed to be an active core and antagonist; testing on heart confirmed these predictions.The active core docking mimicked RhpMS, however, the antagonist did not.

View Article: PubMed Central - PubMed

Affiliation: Undergraduate Biochemistry Program, Chemistry Department, University of Michigan, Ann Arbor, Michigan, United States of America, 48109; Biological Chemistry Department, University of Michigan Medical School, Ann Arbor, Michigan, United States of America, 48109.

ABSTRACT
Peptidergic signaling regulates cardiac contractility; thus, identifying molecular switches, ligand-receptor contacts, and antagonists aids in exploring the underlying mechanisms to influence health. Myosuppressin (MS), a decapeptide, diminishes cardiac contractility and gut motility. Myosuppressin binds to G protein-coupled receptor (GPCR) proteins. Two Drosophila melanogaster myosuppressin receptors (DrmMS-Rs) exist; however, no mechanism underlying MS-R activation is reported. We predicted DrmMS-Rs contained molecular switches that resembled those of Rhodopsin. Additionally, we believed DrmMS-DrmMS-R1 and DrmMS-DrmMS-R2 interactions would reflect our structure-activity relationship (SAR) data. We hypothesized agonist- and antagonist-receptor contacts would differ from one another depending on activity. Lastly, we expected our study to apply to other species; we tested this hypothesis in Rhodnius prolixus, the Chagas disease vector. Searching DrmMS-Rs for molecular switches led to the discovery of a unique ionic lock and a novel 3-6 lock, as well as transmission and tyrosine toggle switches. The DrmMS-DrmMS-R1 and DrmMS-DrmMS-R2 contacts suggested tissue-specific signaling existed, which was in line with our SAR data. We identified R. prolixus (Rhp)MS-R and discovered it, too, contained the unique myosuppressin ionic lock and novel 3-6 lock found in DrmMS-Rs as well as transmission and tyrosine toggle switches. Further, these motifs were present in red flour beetle, common water flea, honey bee, domestic silkworm, and termite MS-Rs. RhpMS and DrmMS decreased R. prolixus cardiac contractility dose dependently with EC50 values of 140 nM and 50 nM. Based on ligand-receptor contacts, we designed RhpMS analogs believed to be an active core and antagonist; testing on heart confirmed these predictions. The active core docking mimicked RhpMS, however, the antagonist did not. Together, these data were consistent with the unique ionic lock, novel 3-6 lock, transmission switch, and tyrosine toggle switch being involved in mechanisms underlying TM movement and MS-R activation, and the ability of MS agonists and antagonists to influence physiology.

No MeSH data available.


Related in: MedlinePlus