Roughly one-third of all proteins reside in biological membranes [1, 2]. Integral membrane proteins (IMPs), which can only be released from the membrane by disruption of the membrane, perform a host of vital cellular functions as receptors, transporters, channels, electrical and photo-transducers, and so forth [3-5]. It is therefore not surprising that mutations in membrane proteins are linked to many diseases and that IMPs represent well over 50% of the targets for existing drugs [6-9]. In spite of the importance of IMPs, the structural biology of this class of proteins remains underdeveloped. As of February 2009 only 1.7 % of the structures deposited into the RSB Protein Data Bank were IMPs based on the searches performed by the PDBTM (pdbtm.enzim.hu) and OPM (opm.phar.umich.edu) [10, 11]. IMPs can be classified based on the dominant secondary structures of their transmembrane domains [10, 11], where the number of IMPs of known structure that utilize α-helical spanning elements clearly outnumbers the number of β-barrel proteins by roughly 4:1 (http://pdbtm.enzim.hu and http://opm.phar.umich.edu). Currently deposited structures also show a clear bias regarding the source organism, with 70% from prokaryotic organisms and 30% from eukaryotic organisms (based upon the PDBTM holdings for non-redundant, experimentally determined structures containing at least one transmembrane element). The total number of integral membrane protein structures determined has accelerated during the decade leading up to 2009, thanks largely to the accomplishments of X-ray crystallography. However in just the past three years, there has been remarkable progress in the application of solution NMR methods to IMPs. Moreover, there is reason to believe that this recent progress reflects only the beginning of a phase of exponential growth in the use of solution NMR methods to solve important problems in membrane protein structural biology. Here, we build upon previous reviews from this laboratory [12, 13] to highlight recent progress in the application of solution NMR of IMPs and to outline sample preparative and spectroscopic advances that have led to this breakthrough. The authors also note with admiration that progress in solution NMR applications has been paralleled by truly remarkable advances in the application of solid state NMR methods to IMPs, as recently reviewed by others [14-19].

中文翻译：

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溶液核磁共振波谱在多跨度整合膜蛋白中应用的最新进展

大约三分之一的蛋白质存在于生物膜中 [1, 2]。整合膜蛋白 (IMP) 只能通过破坏膜才能从膜中释放出来，它执行着许多重要的细胞功能，如受体、转运蛋白、通道、电和光传感器等 [3-5]。因此，膜蛋白中的突变与许多疾病有关并且 IMP 占现有药物靶点的 50% 以上也就不足为奇了 [6-9]。尽管 IMP 很重要，但这类蛋白质的结构生物学仍然不发达。根据 PDBTM (pdbtm.enzim.hu) 和 OPM (opm.phar.umich.edu) [10, 11] 执行的搜索，截至 2009 年 2 月，存入 RSB 蛋白质数据库的结构中只有 1.7% 是 IMP . IMPs 可以根据其跨膜结构域的主要二级结构进行分类 [10, 11]，其中利用 α-螺旋跨越元件的已知结构的 IMPs 的数量明显超过 β-桶蛋白的数量大约 4:1（ http://pdbtm.enzim.hu 和 http://opm.phar.umich.edu）。当前存放的结构也显示出对源生物的明显偏见，其中 70% 来自原核生物，30% 来自真核生物（基于 PDBTM 持有的非冗余、实验确定的结构，其中包含至少一种跨膜元素）。在 2009 年之前的十年中，确定的完整膜蛋白结构的总数有所增加，这在很大程度上要归功于 X 射线晶体学的成就。然而仅仅在过去的三年里，在将溶液核磁共振方法应用于 IMP 方面取得了显着进展。此外，有理由相信，最近的这一进展仅反映了使用溶液核磁共振方法解决膜蛋白结构生物学中重要问题的指数增长阶段的开始。在这里，我们基于该实验室 [12, 13] 之前的评论，重点介绍 IMP 溶液 NMR 应用的最新进展，并概述导致这一突破的样品制备和光谱学进展。作者还钦佩地注意到溶液 NMR 应用的进展与固态 NMR 方法在 IMP 应用方面的真正显着进步并行，正如其他人最近评论的那样 [14-19]。有理由相信，最近的这一进展仅反映了使用溶液核磁共振方法解决膜蛋白结构生物学中重要问题的指数增长阶段的开始。在这里，我们基于该实验室 [12, 13] 之前的评论，重点介绍 IMP 溶液 NMR 应用的最新进展，并概述导致这一突破的样品制备和光谱学进展。作者还钦佩地注意到溶液 NMR 应用的进展与固态 NMR 方法在 IMP 应用方面的真正显着进步并行，正如其他人最近评论的那样 [14-19]。有理由相信，最近的这一进展仅反映了使用溶液核磁共振方法解决膜蛋白结构生物学中重要问题的指数增长阶段的开始。在这里，我们基于该实验室 [12, 13] 之前的评论，重点介绍 IMP 溶液 NMR 应用的最新进展，并概述导致这一突破的样品制备和光谱学进展。作者还钦佩地注意到溶液 NMR 应用的进展与固态 NMR 方法在 IMP 应用方面的真正显着进步并行，正如其他人最近评论的那样 [14-19]。