Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling.
Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling.
复制标题
DOI：
10.1371/journal.pone.0120492
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Nichols R
中科院分区：
文献类型：
--
作者：
Leander M;Bass C;Marchetti K;Maynard BF;Wulff JP;Ons S;Nichols R
肽能信号调节心脏收缩力;因此，识别分子开关，配体-受体接触和拮抗剂有助于探索影响健康的潜在机制。肌抑制素（MS）是一种十肽，可降低心肌收缩力和肠道运动。肌抑制素与G蛋白偶联受体（GPCR）蛋白结合。存在两种果蝇肌抑制素受体（DrmMS-Rs）;然而，没有报道MS-R激活的潜在机制。我们预测DrmMS-Rs含有类似于视紫红质的分子开关。此外，我们认为DrmMS-DrmMS-R1和DrmMS-DrmMS-R2相互作用将反映我们的构效关系（SAR）数据。我们假设激动剂和拮抗剂受体的接触将根据活动而彼此不同。最后，我们希望我们的研究适用于其他物种;我们在Rhodnius prolixus，查加斯病载体中测试了这一假设。在DrmMS-Rs中搜索分子开关，发现了一种独特的离子锁和一种新的3-6锁，以及传输和酪氨酸拨动开关。DrmMS-DrmMS-R1和DrmMS-DrmMS-R2接触表明存在组织特异性信号传导，这与我们的SAR数据一致。我们确定了R。prolixus（Rhp）MS-R，并发现它也含有在DrmMS-R中发现的独特的肌抑制素离子锁和新的3-6锁以及传输和酪氨酸拨动开关。此外，这些基序存在于红粉甲虫、普通水蚤、蜜蜂、家蚕和白蚁MS-Rs中。RhpMS和DrmMS降低R. prolixus心肌收缩力呈剂量依赖性，EC 50值为140 nM和50 nM。基于配体-受体接触，我们设计了被认为是活性核心和拮抗剂的RhpMS类似物;对心脏的测试证实了这些预测。活性核心对接模拟RhpMS，然而，拮抗剂没有。总之，这些数据与TM运动和MS-R激活的潜在机制中涉及的独特离子锁、新型3-6锁、传输开关和酪氨酸拨动开关以及MS激动剂和拮抗剂影响生理学的能力一致。
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.
登录
查看更多内容
影响因子：
2.6
作者：
Ons, S.;Sterkel, M.;Rivera-Pomar, R.
通讯作者：
Rivera-Pomar, R.
DOI：
10.1590/s0074-02762009000900005
发表时间：
2009-07-01
期刊：
Memórias do Instituto Oswaldo Cruz
影响因子：
--
作者：
Moncayo, Álvaro;Silveira, Antonio Carlos
通讯作者：
Silveira, Antonio Carlos
影响因子：
14.8
作者：
通讯作者：
--
影响因子：
3
作者：
Trott, Oleg;Olson, Arthur J.
通讯作者：
Olson, Arthur J.
影响因子：
3
作者：
Morris, Garrett M.;Huey, Ruth;Lindstrom, William;Sanner, Michel F.;Belew, Richard K.;Goodsell, David S.;Olson, Arthur J.
通讯作者：
Olson, Arthur J.