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Flexibility and extracellular opening determine the interaction between ligands and insect sulfakinin receptors.

Yu N, Zotti MJ, Scheys F, Braz AS, Penna PH, Nachman RJ, Smagghe G - Sci Rep (2015)

Bottom Line: TcSKR1 contained a larger outer opening of the cavity than that in TcSKR2, which allows ligands a deep access into the cavity through cell membrane.Second, normal mode analysis revealed that TcSKR1 was more flexible than TcSKR2 during receptor-ligand interaction.Third, the sulfated SK (sSK) and sSK-related peptides were more potent than the nonsulfated SK, suggesting the importance of the sulfate moiety.

View Article: PubMed Central - PubMed

Affiliation: Department of Crop Protection, Faculty of Bioscience Engineering, Ghent University, 9000 Ghent, Belgium.

ABSTRACT
Despite their fundamental importance for growth, the mechanisms that regulate food intake are poorly understood. Our previous work demonstrated that insect sulfakinin (SK) signaling is involved in inhibiting feeding in an important model and pest insect, the red flour beetle Tribolium castaneum. Because the interaction of SK peptide and SK receptors (SKR) initiates the SK signaling, we have special interest on the structural factors that influence the SK-SKR interaction. First, the three-dimensional structures of the two T. castaneum SKRs (TcSKR1 and TcSKR2) were generated from molecular modeling and they displayed significance in terms of the outer opening of the cavity and protein flexibility. TcSKR1 contained a larger outer opening of the cavity than that in TcSKR2, which allows ligands a deep access into the cavity through cell membrane. Second, normal mode analysis revealed that TcSKR1 was more flexible than TcSKR2 during receptor-ligand interaction. Third, the sulfated SK (sSK) and sSK-related peptides were more potent than the nonsulfated SK, suggesting the importance of the sulfate moiety.

No MeSH data available.


Related in: MedlinePlus

Flexibility demonstrated by a graph constructed using root-mean-square fluctuation (RMSF) for each amino acid in TcSKR1 model (A) and RMSF plotted onto TcSKR1 structure (B–D). The corresponding amino acids for TcSKR1 are indicated along with the x-axis. The calculations were performed with empty cavity of TcSKR1 in oxidized state (SKR1_oxy, black line), with docked nonsulfated sulfakinin (SKR1_oxy_lig_ns, blue line) and with docked sulfated sulfakinin (SKR1_oxy_lig_s, red line) and the retrieved flexibility (RMSF) was plotted onto structures (B–D), respectively. The transparent ellipses indicate regions with remarkable changes. The red ellipse corresponds to transmembrane region I and blue ellipse corresponds to extracellular loop 3. These regions are also indicated in the line graph by a red arrow or blue arrows.
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f3: Flexibility demonstrated by a graph constructed using root-mean-square fluctuation (RMSF) for each amino acid in TcSKR1 model (A) and RMSF plotted onto TcSKR1 structure (B–D). The corresponding amino acids for TcSKR1 are indicated along with the x-axis. The calculations were performed with empty cavity of TcSKR1 in oxidized state (SKR1_oxy, black line), with docked nonsulfated sulfakinin (SKR1_oxy_lig_ns, blue line) and with docked sulfated sulfakinin (SKR1_oxy_lig_s, red line) and the retrieved flexibility (RMSF) was plotted onto structures (B–D), respectively. The transparent ellipses indicate regions with remarkable changes. The red ellipse corresponds to transmembrane region I and blue ellipse corresponds to extracellular loop 3. These regions are also indicated in the line graph by a red arrow or blue arrows.

Mentions: In the present project, we also used NMA to investigate structural variation in the flexibility of TcSKR1 imposed by sSK and nsSK. The two forms of SK introduced specific variations at very much defined regions (Fig. 3A). Transmembrane I (TM I, red ellipse in Fig. 3) showed a steadily increase in flexibility from receptor with empty cavity, with docked nsSK and with docked sSK (Fig. 3B–D, respectively). sSK introduced a considerable stabilization in ECL 3 (Fig. 3D). The ECLs (blue ellipse in Fig. 3) showed medium flexibility in receptor with empty cavity, decreased the flexibility in receptor with docked nsSK, and became almost rigid in the receptor with docked sSK (Fig. 3B–D, respectively). Both receptor models were stable during 200 ns of molecular dynamics, with variation of backbone (RMDS) around 0.3 nm (Supplementary figure 1). Nevertheless we noted that SKR1 is more stable when peptides occupy the cavity.


Flexibility and extracellular opening determine the interaction between ligands and insect sulfakinin receptors.

Yu N, Zotti MJ, Scheys F, Braz AS, Penna PH, Nachman RJ, Smagghe G - Sci Rep (2015)

Flexibility demonstrated by a graph constructed using root-mean-square fluctuation (RMSF) for each amino acid in TcSKR1 model (A) and RMSF plotted onto TcSKR1 structure (B–D). The corresponding amino acids for TcSKR1 are indicated along with the x-axis. The calculations were performed with empty cavity of TcSKR1 in oxidized state (SKR1_oxy, black line), with docked nonsulfated sulfakinin (SKR1_oxy_lig_ns, blue line) and with docked sulfated sulfakinin (SKR1_oxy_lig_s, red line) and the retrieved flexibility (RMSF) was plotted onto structures (B–D), respectively. The transparent ellipses indicate regions with remarkable changes. The red ellipse corresponds to transmembrane region I and blue ellipse corresponds to extracellular loop 3. These regions are also indicated in the line graph by a red arrow or blue arrows.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4542541&req=5

f3: Flexibility demonstrated by a graph constructed using root-mean-square fluctuation (RMSF) for each amino acid in TcSKR1 model (A) and RMSF plotted onto TcSKR1 structure (B–D). The corresponding amino acids for TcSKR1 are indicated along with the x-axis. The calculations were performed with empty cavity of TcSKR1 in oxidized state (SKR1_oxy, black line), with docked nonsulfated sulfakinin (SKR1_oxy_lig_ns, blue line) and with docked sulfated sulfakinin (SKR1_oxy_lig_s, red line) and the retrieved flexibility (RMSF) was plotted onto structures (B–D), respectively. The transparent ellipses indicate regions with remarkable changes. The red ellipse corresponds to transmembrane region I and blue ellipse corresponds to extracellular loop 3. These regions are also indicated in the line graph by a red arrow or blue arrows.
Mentions: In the present project, we also used NMA to investigate structural variation in the flexibility of TcSKR1 imposed by sSK and nsSK. The two forms of SK introduced specific variations at very much defined regions (Fig. 3A). Transmembrane I (TM I, red ellipse in Fig. 3) showed a steadily increase in flexibility from receptor with empty cavity, with docked nsSK and with docked sSK (Fig. 3B–D, respectively). sSK introduced a considerable stabilization in ECL 3 (Fig. 3D). The ECLs (blue ellipse in Fig. 3) showed medium flexibility in receptor with empty cavity, decreased the flexibility in receptor with docked nsSK, and became almost rigid in the receptor with docked sSK (Fig. 3B–D, respectively). Both receptor models were stable during 200 ns of molecular dynamics, with variation of backbone (RMDS) around 0.3 nm (Supplementary figure 1). Nevertheless we noted that SKR1 is more stable when peptides occupy the cavity.

Bottom Line: TcSKR1 contained a larger outer opening of the cavity than that in TcSKR2, which allows ligands a deep access into the cavity through cell membrane.Second, normal mode analysis revealed that TcSKR1 was more flexible than TcSKR2 during receptor-ligand interaction.Third, the sulfated SK (sSK) and sSK-related peptides were more potent than the nonsulfated SK, suggesting the importance of the sulfate moiety.

View Article: PubMed Central - PubMed

Affiliation: Department of Crop Protection, Faculty of Bioscience Engineering, Ghent University, 9000 Ghent, Belgium.

ABSTRACT
Despite their fundamental importance for growth, the mechanisms that regulate food intake are poorly understood. Our previous work demonstrated that insect sulfakinin (SK) signaling is involved in inhibiting feeding in an important model and pest insect, the red flour beetle Tribolium castaneum. Because the interaction of SK peptide and SK receptors (SKR) initiates the SK signaling, we have special interest on the structural factors that influence the SK-SKR interaction. First, the three-dimensional structures of the two T. castaneum SKRs (TcSKR1 and TcSKR2) were generated from molecular modeling and they displayed significance in terms of the outer opening of the cavity and protein flexibility. TcSKR1 contained a larger outer opening of the cavity than that in TcSKR2, which allows ligands a deep access into the cavity through cell membrane. Second, normal mode analysis revealed that TcSKR1 was more flexible than TcSKR2 during receptor-ligand interaction. Third, the sulfated SK (sSK) and sSK-related peptides were more potent than the nonsulfated SK, suggesting the importance of the sulfate moiety.

No MeSH data available.


Related in: MedlinePlus