基于活性探针分子对代谢型γ-氨基丁酸受体激活机制的研究
摘要
G蛋白偶联受体（GPCRs）在体内介导着多种配体引起的生理反应，如激素、神经递质和感官刺激。我们设计并合成了针对GABA_B受体的具有活性和光亲和力的分子探针。以探针为基础，我们能够将GABA_B受体锁定在非活性构象上，然后通过正向变构剂来激活受体。从而能够对与GABA_B受体激活相关的动态事件进行监测。我们发现，GABA_B受体能够调控一个包含有GABA_B受体、IGF-1R及其下游效应物在内的蛋白复合物发生一系列动态变化。其中值得注意的是，G蛋白能够与静息状态下的GABA_B受体预偶联（pre-coupling），并在受体激活后迅速解离。我们还发现，这种复合物的动态变化过程是GABA_B受体激活的关键。我们的研究确定了一系列GABA_B受体与下游型号蛋白间的相互作用，它们对于受体的激活非常关键。
GABA_(B1)亚基的胞外结构域（GABA_(B1)-VFT）包含有配体结合位点（LBP），是一个非常好的药物治疗靶点。为了对其结构开展进一步的研究，我们大量表达并纯化了GABA_(B1)-VFT重组蛋白。并且用配体亲和层析解决了重组蛋白的低活性问题，成功地分离出了高活性的GABA_(B1)-VFT蛋白。
同时，为了研究GABA_B受体与配体的结合过程，我们设计了一个采用电喷雾质谱、圆二色谱和荧光光谱等技术来监控蛋白质与配体结合过程中其二级结构和三级结构变化的平台。在这个平台上，我们分析了了肌红蛋白在不同环境下与配体结合和解离的过程。并发现由酸和有机溶剂引起的肌红蛋白的血红素解离现象具有不同的内在机制。
G protein-coupled receptors (GPCRs) mediate physiological responses to variousligands, such as hormones, neurotransmitters and sensory stimuli. We synthesized bothactive and affinity tagged photo-affinity probes specific to GABA_Breceptor. Suchactivity-based probes enabled us to first lock GABA_Breceptor in an inactive state and thenstimulate the receptor with a positive allosteric modulator, thereby permitting monitoringof the dynamic events associated with GABA_Breceptor activation. We found thatactivation of GABA_Breceptor triggered a dynamic assembly and disassembly of a proteincomplex, including GABA_Breceptor, IGF-1R and its downstream effectors. Notably, bothGαi and Gβ s ubunits were pre-assembled with the inactive GABA_Breceptor anddisassembled from the receptor complex upon activation. Our results identify a criticalrole for activity-specified dynamic protein interactions between GABA_Breceptor anddownstream signaling proteins.
The extracellular domain of GABA_(B1)subunit (GABA_(B1)-VFT) contains the Ligandbinding pocket (LBP) and was an excellent therapeutic target. For the further researches ofthe GABA_(B1)-VFT domain structure, the recombinant GABA_(B1)-VFT was cloned,expressed and purified in large scale. The functional fraction of GABA_(B1)-VFT wasisolated by the ligand affinity chromatography. This fraction has the high activity ofligand binding.
In order to study the process of GABA_Breceptor ligand bind, we designed a platformconstructed by ESI-MS, Circular Dichroism Spectroscopy and Fluorescence Spectroscopywhich can monitor the Secondary structure and the Tertiary structure changes as well asthe ligands binding or dissociation process. With this platform, we analyzed the Mbconformational changes during its ligand binding or dissociation process in differentconditions, and demonstrated the different mechanism of the heme releasing induced byacid and organic solvents.
GABA_(B1)亚基的胞外结构域（GABA_(B1)-VFT）包含有配体结合位点（LBP），是一个非常好的药物治疗靶点。为了对其结构开展进一步的研究，我们大量表达并纯化了GABA_(B1)-VFT重组蛋白。并且用配体亲和层析解决了重组蛋白的低活性问题，成功地分离出了高活性的GABA_(B1)-VFT蛋白。
同时，为了研究GABA_B受体与配体的结合过程，我们设计了一个采用电喷雾质谱、圆二色谱和荧光光谱等技术来监控蛋白质与配体结合过程中其二级结构和三级结构变化的平台。在这个平台上，我们分析了了肌红蛋白在不同环境下与配体结合和解离的过程。并发现由酸和有机溶剂引起的肌红蛋白的血红素解离现象具有不同的内在机制。
G protein-coupled receptors (GPCRs) mediate physiological responses to variousligands, such as hormones, neurotransmitters and sensory stimuli. We synthesized bothactive and affinity tagged photo-affinity probes specific to GABA_Breceptor. Suchactivity-based probes enabled us to first lock GABA_Breceptor in an inactive state and thenstimulate the receptor with a positive allosteric modulator, thereby permitting monitoringof the dynamic events associated with GABA_Breceptor activation. We found thatactivation of GABA_Breceptor triggered a dynamic assembly and disassembly of a proteincomplex, including GABA_Breceptor, IGF-1R and its downstream effectors. Notably, bothGαi and Gβ s ubunits were pre-assembled with the inactive GABA_Breceptor anddisassembled from the receptor complex upon activation. Our results identify a criticalrole for activity-specified dynamic protein interactions between GABA_Breceptor anddownstream signaling proteins.
The extracellular domain of GABA_(B1)subunit (GABA_(B1)-VFT) contains the Ligandbinding pocket (LBP) and was an excellent therapeutic target. For the further researches ofthe GABA_(B1)-VFT domain structure, the recombinant GABA_(B1)-VFT was cloned,expressed and purified in large scale. The functional fraction of GABA_(B1)-VFT wasisolated by the ligand affinity chromatography. This fraction has the high activity ofligand binding.
In order to study the process of GABA_Breceptor ligand bind, we designed a platformconstructed by ESI-MS, Circular Dichroism Spectroscopy and Fluorescence Spectroscopywhich can monitor the Secondary structure and the Tertiary structure changes as well asthe ligands binding or dissociation process. With this platform, we analyzed the Mbconformational changes during its ligand binding or dissociation process in differentconditions, and demonstrated the different mechanism of the heme releasing induced byacid and organic solvents.
引文
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