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G蛋白偶联受体二聚化研究进展 总被引:1,自引:0,他引:1
G蛋白偶联受体是细胞膜受体最大的家族,参与调节多种生理过程,在信号识别及转导中具有重要作用,传统观点认为G蛋白偶联受体作为单体起作用,近年来,越来越多的证据表明,G蛋白偶联受体不仅能以二聚体形式存在,而且在细胞信号转导中起重要作用,尤其是对阿片受体异源二聚体的研究,推动了这一领域的研究。本文综述了G蛋白偶联受体二聚化研究进展,以及同源和异源二聚体的结构与功能。 相似文献
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孤儿G蛋白偶联受体研究进展 总被引:3,自引:0,他引:3
孤儿G蛋白偶联受体的研究意味着发现其尚未了解的内源性配体,是后基因组时代功能基因组学研究的热点之一,对生命科学的发展具有深 影响。本文介绍孤儿G蛋白偶联受体的概念、研究策略及其应用。 相似文献
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G蛋白偶联受体(G protein-coupled receptors,GPCRs)是一类重要的细胞膜表面跨膜蛋白受体超家族,具有7个跨膜螺旋结构。GPCRs的细胞内信号由G蛋白介导,可将激素、神经递质、药物、趋化因子等多种物理和化学的细胞外刺激穿过细胞膜转导到细胞内不同的效应分子,激活相应的信号级联系统进而影响恶性肿瘤的生长迁移过程。虽然目前药物市场上有很多治疗癌症的小分子药物属于G蛋白受体相关药物,但所作用的靶点集中于少数特定G蛋白偶联受体。因此,新的具有成药性的G蛋白偶联受体的开发具有很大的研究价值和市场潜力。本文主要以在癌症发生、发展中起重要作用的溶血磷脂酸(LPA),G蛋白偶联受体30(GPR30)、内皮素A受体(ETAR)等不同G蛋白偶联受体为分类依据,综述其与相关的信号通路在癌症进程中的作用,并对相应的小分子药物的临床应用和研究进展进行展望。 相似文献
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G蛋白偶联受体的研究进展 总被引:1,自引:0,他引:1
G蛋白偶联受体(GPCRs),是体内最大的蛋白质超家族。GPCRs的基本结构巳清楚,但高分辨率的三维结构还未得到。根据结构的同源性,GPCRs主要分为A、B、C3族。GPCRs配体的多样性决定配体结合域的多样性。受体分子内相互作用力的破坏,质子化,构象变化,与G蛋白的偶联以及受体二聚化参与了GPCRs的活化过程。GPCRs的活化模式有3种;二态模式、多态模式和顺序结合的构象选择模式。 相似文献
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G蛋白偶联受体激酶(G protein-coupled receptor kinase,GRK)特异地使活化的G蛋白偶联受体(G protein-coupled receptor,GPCR)发生磷酸化及脱敏化,从而终止后者介导的信号转导通路。研究表明,GRK的功能被高度调控,并具有下行调节GPCR的能力。调控GRK功能的机制包括两个层次:(1)多种途径调控激酶的亚细胞定位及活性,包括GPCR介导、G蛋白偶联、磷脂作用、Ca^2 结合蛋白调控、蛋白激酶C活化、MAPK反馈抑制、小窝蛋白抑制等;(2)调控GRK表达水平,主要体现在其与某些疾病的联系。 相似文献
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植物病原丝状真菌G蛋白偶联受体的研究进展 总被引:1,自引:0,他引:1
通过对丝状真菌G蛋白偶联受体(GPCR)的结构、分类以及功能方面进行综述,以期明确丝状真菌与其他模式生物GPCR之间的关系。基于已报道的模式生物及丝状真菌等不同生物中的GPCR,通过SMART保守结构域分析,以及利用Clustal X、MEGA等软件对上述GPCR进行遗传关系分析。明确丝状真菌典型GPCR具有七跨膜结构域,新型GPCR则含有PIPK、RGS等保守结构域,明确不同学者对于GPCR的分类情况,以及新型GPCR所具有的特殊功能,明确模式生物GPCR、丝状真菌GPCR分别各自聚类。丝状真菌中GPCR的数量较模式生物少,不同分类单元中真菌之间GPCR的数量也不尽相同,同时,丝状真菌GPCR除具有典型的七跨膜结构域外,还含有一些其他保守的结构域,上述研究为进一步开展其功能研究提供重要的理论基础。 相似文献
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G蛋白偶联受体(GPCR)是细胞膜上最大的一类受体,其通过构象变化激活下游G蛋白从而介导细胞响应多种来自内源和外界环境中的信号。自GPCR被发现以来,研究者就一直在努力解析GPCR的构象,x射线晶体衍射技术和GPCR蛋白质结晶技术的发展使得越来越多的GPCR单体在静息状态,以及与不同配体甚至G蛋白结合的晶体结构被成功解析。另一方面,FRET和电子显微技术的运用得到了GPCR二聚化和多聚化的多方面证据。本文将结合近年来该领域的进展,对GPCR寡聚体的结构和构象变化予以系统的综述,这些成果为研究GPCR的功能机制及其特异性的靶点药物开发提供了重要的基础。 相似文献
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G蛋白偶联受体是体内最大的受体超家族,它们参与调节生物体内多种生理功能与病理过程。G蛋白偶联受体的分子内构象变化与G蛋白的偶联以及受体的二聚化等是G蛋白偶联受体激活的重要基本过程。借助于单分予研究手段,在G蛋白偶联受体激活方面取得了重要进展。本文将就这些方面进行简要的综述。 相似文献
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《Bioorganic & medicinal chemistry》2016,24(23):6139-6148
Detection of cerebral β-amyloid (Aβ) by targeted contrast agents is of great interest for in vivo diagnosis of Alzheimer’s disease (AD). Partly because of their planar structure several bis-styrylbenzenes have been previously reported as potential Aβ imaging agents. However, these compounds are relatively hydrophobic, which likely limits their in vivo potential. Based on their structures, we hypothesized that less hydrophobic bis-pyridylethenylbenzenes may also label amyloid. We synthesized several bis-pyridylethenylbenzenes and tested whether these compounds indeed display improved solubility and lower Log P values, and studied their fluorescent properties and Aβ binding characteristics. Bis-pyridylethenylbenzenes showed a clear affinity for Aβ plaques on both human and murine AD brain sections. Competitive binding experiments suggested a different binding site than Chrysamine G, a well-known stain for amyloid. With a Log P value between 3 and 5, most bis-pyridylethenylbenzenes were able to enter the brain and label murine amyloid in vivo with the bis(4-pyridylethenyl)benzenes showing the most favorable characteristics. In conclusion, the presented results suggest that bis-pyridylethenylbenzene may serve as a novel backbone for amyloid imaging agents. 相似文献
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Seong Rim Byeon Hyunjin Vincent Kim Mijin Jeon Young Gil Ahn Maeng Sup Kim Jae Yang Kong Hye Yun Kim Young Soo Kim Dong Jin Kim 《Bioorganic & medicinal chemistry letters》2013,23(11):3467-3469
Alzheimer’s disease drug discovery regarding exploration into the molecules and processes has focused on the intrinsic causes of the brain disorder correlated with the accumulation of amyloid-β. An anti-amyloidogenic bis-styrylbenzene derivative, KMS80013, showed excellent oral bioavailability (F = 46.2%), facilitated brain penetration (26%, iv) in mouse and target specific in vivo efficacy in acute AD mouse model attenuating the cognitive deficiency in Y-maze test. Acute toxicity (LD50 >2000 mg/kg) and hERG channel inhibition (14% at 10 μM) results indicated safety of KMS80013. 相似文献
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CAMILA DALE NATHALIE VERGNOLLE 《Journal of receptor and signal transduction research》2013,33(1-2):29-37
Proteases, like thrombin, trypsin, cathepsins, or tryptase, can signal to cells by cleaving in a specific manner, a family of G protein-coupled receptors, the protease-activated receptors (PARs). Proteases cleave the extracellular N-terminal domain of PARs to reveal tethered ligand domains that bind to and activate the receptors. Recent evidence has supported the involvement of PARs in inflammation and pain. Activation of PAR1, PAR2, and PAR4 either by proteinases or by selective agonists causes inflammation inducing most of the cardinal signs of inflammation: swelling, redness, and pain. Recent studies suggest a crucial role for the different PARs in innate immune response. The role of PARs in the activation of pain pathways appears to be dual. Subinflammatory doses of PAR2 agonists induce hyperalgesia and allodynia, and PAR2 activation has been implicated in the generation of inflammatory hyperalgesia. In contrast, subinflammatory doses of PAR1 or PAR4 increase nociceptive threshold, inhibiting inflammatory hyperalgesia, thereby acting as analgesic mediators. PARs have to be considered as an additional subclass of G protein-coupled receptors that are active participants to inflammation and pain responses and that could constitute potential novel therapeutic targets. 相似文献
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《Bioorganic & medicinal chemistry》2020,28(13):115559
Amyloid-β oligomers (AβOs) enrichment in brain is highly related to Alzheimer’s pathogenesis, but tracing them in the brain by imaging technique is still a great challenge due to their heterogeneity and metastability. Herein, a new near-infrared (NIR) fluorescent probe, namely, PTO-41, was designed and synthesized to specifically target AβOs. PTO-41 possesses excellent functional properties including optimal fluorescent properties (emission maxima at 680 nm upon interacting with AβOs), high affinity (Kd = 349 nM), low cell toxicity, desirable lipophilicity (log P = 2.24), and fast wash out from the brain (brain2 min/brain60 min = 5.0). Furthermore, PTO-41 exhibits a high sensitivity toward AβOs in vitro phantom imaging experiments. More importantly, PTO-41 shows great capacity to differentiate between 4-month-old APP/PS1 model mice from age-matched control mice using in vivo imaging. In summary, PTO-41 almost meets all the requirements as a versatile NIR fluorescent probe for the detection of AβOs both in vitro and in vivo. 相似文献
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《Bioorganic & medicinal chemistry》2020,28(11):115455
Gamma-secretase modulators (GSMs) selectively lower amyloid-β42 (Aβ42) and are therefore potential disease-modifying drugs for Alzheimer’s disease (AD). Here, we report the discovery of imidazopyridine derivatives as GSMs with oral activity on not only Aβ42 levels but also cognitive function. Structural optimization of the biphenyl group and pyridine-2-amide moiety of compound 1a greatly improved GSM activity and rat microsomal stability, respectively. 5-{8-[(3,4′-Difluoro[1,1′-biphenyl]-4-yl)methoxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-N-methylpyridine-2-carboxamide (1o) showed high in vitro potency and brain exposure, induced a robust reduction in brain Aβ42 levels, and exhibited undetectable inhibition of cytochrome p450 enzymes. Moreover, compound 1o showed excellent efficacy against cognitive deficits in AD model mice. These findings suggest that compound 1o is a promising candidate for AD therapeutics. 相似文献
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《Bioorganic & medicinal chemistry》2016,24(18):4138-4143
Two hallmarks of Alzheimer’s disease (AD) observed in the brains of patients with the disease include oxidative injury and deposition of protein aggregates comprised of amyloid-β (Aβ) variants. To inhibit these toxic processes, we synthesized antioxidant-conjugated peptides comprised of Trolox and various C-terminal motifs of Aβ variants, TxAβx–n (x = 34, 36, 38, 40; n = 40, 42, 43). Most of these compounds were found to exhibit anti-aggregation activities. Among them, TxAβ36–42 significantly inhibited Aβ1–42 aggregation, showed potent antioxidant activity, and protected SH-SY5Y cells from Aβ1–42-induced cytotoxicity. Thus, this method represents a promising strategy for developing multifunctional AD therapeutic agents. 相似文献