Topiol Sid, Sabio Michael
Department of Computational Chemistry, Lundbeck Research USA, Inc., 215 College Road, Paramus, NJ 07652, USA.
Biochem Pharmacol. 2009 Jul 1;78(1):11-20. doi: 10.1016/j.bcp.2009.02.012. Epub 2009 Feb 27.
G-protein-coupled receptor (GPCR) proteins [Lundstrom KH, Chiu ML, editors. G protein-coupled receptors in drug discovery. CRC Press; 2006] are the single largest drug target, representing 25-50% of marketed drugs [Overington JP, Al-Lazikani B, Hopkins AL. How many drug targets are there? Nat Rev Drug Discov 2006;5(12):993-6; Parrill AL. Crystal structures of a second G protein-coupled receptor: triumphs and implications. ChemMedChem 2008;3:1021-3]. While there are six subclasses of GPCR proteins, the hallmark of all GPCR proteins is the transmembrane-spanning region. The general architecture of this transmembrane (TM) region has been known for some time to contain seven alpha-helices. From a drug discovery and design perspective, structural information of the GPCRs has been sought as a tool for structure-based drug design. The advances in the past decade of technologies for structure-based design have proven to be useful in a number of areas. Invoking these approaches for GPCR targets has remained challenging. Until recently, the most closely related structures available for GPCR modeling have been those of bovine rhodopsin. While a representative of class A GPCRs, bovine rhodopsin is not a ligand-activated GPCR and is fairly distant in sequence homology to other class A GPCRs. Thus, there is a variable degree of uncertainty in the use of the rhodopsin X-ray structure as a template for homology modeling of other GPCR targets. Recent publications of X-ray structures of class A GPCRs now offer the opportunity to better understand the molecular mechanism of action at the atomic level, to deploy X-ray structures directly for their use in structure-based design, and to provide more promising templates for many other ligand-mediated GPCRs. We summarize herein some of the recent findings in this area and provide an initial perspective of the emerging opportunities, possible limitations, and remaining questions. Other aspects of the recent X-ray structures are described by Weis and Kobilka [Weis WI, Kobilka BK. Structural insights into G-protein-coupled receptor activation. Curr Opin Struct Biol 2008;18:734-40] and Mustafi and Palczewski [Mustafi D, Palczewski K. Topology of class A G protein-coupled receptors: insights gained from crystal structures of rhodopsins, adrenergic and adenosine receptors. Mol Pharmacol 2009;75:1-12].
G蛋白偶联受体（GPCR）蛋白[伦德斯特伦KH，邱ML，编辑。药物发现中的G蛋白偶联受体。CRC出版社；2006年]是最大的单一药物靶点，占上市药物的25 - 50%[奥弗林顿JP，阿尔 - 拉齐卡尼B，霍普金斯AL。有多少药物靶点？《自然药物发现评论》2006年；5（12）：993 - 996；帕里尔AL。第二个G蛋白偶联受体的晶体结构：成就与启示。《化学生物化学》2008年；3：1021 - 103]。虽然GPCR蛋白有六个亚类，但所有GPCR蛋白的标志是跨膜区域。一段时间以来，已知该跨膜（TM）区域的总体结构包含七个α螺旋。从药物发现和设计的角度来看，GPCR的结构信息一直被视为基于结构的药物设计工具。过去十年基于结构设计技术的进展已被证明在许多领域有用。将这些方法应用于GPCR靶点仍然具有挑战性。直到最近，可用于GPCR建模的最密切相关结构是牛视紫红质的结构。虽然牛视紫红质是A类GPCR的代表，但它不是配体激活的GPCR，并且与其他A类GPCR的序列同源性相当远。因此，将视紫红质X射线结构用作其他GPCR靶点同源建模模板存在不同程度的不确定性。最近A类GPCR的X射线结构出版物现在提供了机会，以便在原子水平上更好地理解作用的分子机制，直接将X射线结构用于基于结构的设计，并为许多其他配体介导的GPCR提供更有前景的模板。我们在此总结该领域的一些最新发现，并对新出现的机会、可能的局限性和遗留问题提供初步观点。最近X射线结构的其他方面由魏斯和科比尔卡[魏斯WI，科比尔卡BK。G蛋白偶联受体激活的结构见解。《当代结构生物学观点》2008年；18：734 - 740]以及穆斯塔菲和帕尔采夫斯基[穆斯塔菲D，帕尔采夫斯基K。A类G蛋白偶联受体的拓扑结构：从视紫红质、肾上腺素能和腺苷受体的晶体结构中获得的见解。《分子药理学》2009年；75：1 - 12]进行了描述。
