The seven pillars of molecular pharmacology: GPCR research honored with Nobel Prize for chemistry.
The seven pillars of molecular pharmacology: GPCR research honored with Nobel Prize for chemistry.
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分子药理学的七大支柱：GPCR研究荣获诺贝尔化学奖。
作者：
F. Hausch;F. Holsboer
G 蛋白偶联受体 (GPCR) 是细胞通讯的主力。它们使人类细胞能够感知外部线索，例如光或味道，或通过激素或神经递质相互交谈。它们参与人体的大多数生理过程，并且是当今 30% 以上的处方药的靶标。我们对这类蛋白质的了解大多是由今年的诺贝尔化学奖获得者罗伯特·J·莱夫科维茨 (Robert J. Lefkowitz) 和布莱恩·K·科比尔卡 (Brian K. Kobilka) 的开创性发现推动的。要充分理解这两位 GPCR 先驱的优点，我们必须追溯到 1986 年。当时，药物主要是通过在整个动物或离体器官中测试化合物来发现的。激素、神经递质或药物如何在分子水平上发挥作用很大程度上是未知的。一些主要的常见下游细胞内效应系统（许多激素和药物似乎都集中在这些系统上）已经被解开，例如第二信使或 G 蛋白（图 1）。但激素、神经递质和药物的直接受体的身份尚未被破译。这些未知的受体是能够特异性识别单个配体的关键实体，它们似乎传达了组织特异性，从而传达了小分子的生物学用途。 20 世纪 80 年代最先进技术的一个典型例子是肾上腺素能系统，它曾经是、现在仍然是 Lefkowitz 和 Kobilka 小组的焦点。在莱夫科维茨小组做出贡献之前，已知儿茶酚胺（例如肾上腺素或去甲肾上腺素）可以介导多种生理作用，例如调节血压。儿茶酚胺系统的重要性已得到认识，β-肾上腺素能拮抗剂、β-受体阻滞剂（如普萘洛尔）即将成为医学实践中最成功的药物之一。从机制上讲，早在 20 世纪 80 年代，人们就知道儿茶酚胺（与许多激素和神经递质一样）通过 G 蛋白影响第二信使的产生（图 1）。然而，人们对儿茶酚胺或β-受体阻滞剂的直接靶点知之甚少，更不用说有关其数量、组成或结构的任何进一步细节了。儿茶酚胺受体最强的分子线索是通过功能研究获得的，它们被认为至少由两类组成：a-肾上腺素能受体和b-肾上腺素能受体。 Lefkowitz 及其同事使用新可用的放射性配体通过生物化学方法定义了肾上腺素能受体。这些放射性配体使他们能够通过生化方法追踪各种组织中假定的β-肾上腺素受体的纯化情况。由此，他们获得了第一个具有功能活性的纯巴德雷能受体制剂。这明确表明，b 亚型的儿茶酚胺受体是一种单一蛋白质，包含将儿茶酚胺结合到细胞内部而传递的信息所必需的所有元素。然而，更重要的是，这种纯受体制剂提供了足够量的源自巴德雷能受体的肽用于测序。此时布莱恩·科比尔卡加入了莱夫科维茨小组。他与 Merck Sharp & Dohme 的研究人员合作，从 β 肾上腺素受体肽序列中衍生出寡核苷酸探针，并利用新颖的分子生物学技术，实现了编码 β2 肾上腺素受体 (b2AR) 的基因的分离和测序。 [4]
G protein-coupled receptors (GPCRs) are the working horses of cellular communication. They allow human cells to sense external cues, such as light or taste, or to talk to each other through hormones or neurotransmitters. They are involved in most physiological processes of the human body and are targeted by over 30 % of today s prescription drugs. Much of what we know about this class of proteins was stimulated by seminal discoveries by this year s Nobel Prize laureates for chemistry, Robert J. Lefkowitz and Brian K. Kobilka. To fully appreciate the merits of these two GPCR pioneers one has to go back to the year 1986. At that time drugs were mainly discovered by testing compounds in whole animals or in isolated organs. How hormones, neurotransmitters, or drugs worked at the molecular level was largely unknown. Some major common downstream intracellular effector systems, on which many hormones and drugs seemed to converge, had been unraveled, for example, second messengers or G proteins (Figure 1). But the identity of the direct receptors for hormones, neurotransmitters, and drugs had not been deciphered. Those unknown receptors were the crucial entities that were capable to specifically recognize individual ligands and they seemed to convey the tissue specificity and therefore the biological usefulness of small molecules. A typical example for the state of the art in the 1980s is the adrenergic system, which was, and continues to be, the focus of the Lefkowitz and Kobilka groups. Prior to the contributions of the Lefkowitz group, catecholamines, such as adrenaline or noradrenaline, were known to mediate a variety of physiological effects, such as regulating blood pressure. The importance of the catecholamine system had been recognized and b-adrenergic antagonists, the b-blockers such as propranolol, were about to become one of the most successful drugs in medicinal practice. Mechanistically it was known in the 1980s that catecholamines—like many hormones and neurotransmitters—acted through G proteins on the production of second messengers (Figure 1). However, the direct target(s) of catecholamines or b-blockers were only marginally known, let alone any further details regarding their number, composition, or structure. The strongest molecular clues for catecholamine receptors had been obtained through functional studies and they were thought to consist of at least two classes, the a-adrenergic receptor(s) and the b-adrenergic receptor(s). Lefkowitz and colleagues defined adrenergic receptors biochemically using newly available radioligands. These radioligands allowed them to track biochemically the purification of the putative b-adrenergic receptor from a variety of tissues. Thereby, they were able obtain the first pure badrenergic receptor preparation that was functionally active. This unequivocally showed that the catecholamine receptor of the b-subtype was a single protein that harbored all the elements necessary to transmit the message exerted by catecholamine binding into the inside of cells. Even more importantly, however, this pure-receptor preparation provided sufficient amounts of peptides derived from the badrenergic receptor for sequencing. At this time Brian Kobilka joined the Lefkowitz group. In collaboration with researchers from Merck Sharp & Dohme, he derived oligonucleotide probes from the b-adrenergic receptor peptide sequences and—using novel molecular biology techniques—they achieved the isolation and sequencing of the gene encoding the b2-adrenergic receptor (b2AR). [4]
影响因子：
56.9
作者：
Luttrell, LM;Ferguson, SSG;Lefkowitz, RJ
通讯作者：
Lefkowitz, RJ
影响因子：
56.9
作者：
LOHSE, MJ;BENOVIC, JL;LEFKOWITZ, RJ
通讯作者：
LEFKOWITZ, RJ