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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural and kinetic modeling of an activating helix switch in the rhodopsin-transducin interface
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Structural and kinetic modeling of an activating helix switch in the rhodopsin-transducin interface

机译：视紫红质-转导蛋白界面中的激活螺旋开关的结构和动力学建模

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摘要

Extracellular signals prompt G protein-coupled receptors (GPCRs) to adopt an active conformation (R~*) and catalyze GDP/GTP exchange in the α-subunit of intracellular G proteins (Gaβγ). Kinetic analysis of transducin (G_tαβγ) activation shows that an intermediary R~*·G_tαβγGDP complex is formed that precedes GDP release and formation of the nucleotide-free R~·G protein complex. Based on this reaction sequence, we explore the dynamic interface between the proteins during formation of these complexes. We start from the R~* conformation stabilized by a G_tα C-terminal peptide (GαCT) obtained from crystal structures of the GPCR opsin. Molecular modeling allows reconstruction of the fully elongated C-terminal α-helix of G_tα (α5) and shows how α5 can be docked to the open binding site of R~*. Two modes of interaction are found. One of them - termed stable or S-interaction - matches the position of the GαCT peptide in the crystal structure and reproduces the hydrogen-bonding networks between the C-terminal reverse turn of GαCT and conserved E(D)RY and NPxxY(x)_(5.6)F regions of the-GPCR. The alternative fit - termed intermediary or l-interaction - is distinguished by a tilt (42°) and rotation (90°) of a5 relative to the S-interaction and shows different α5 contacts with the NPxxY(x)_(5.6)F region and the second cytoplasmic loop of R~*. From the 2α5 interactions, we derive a "helix switch" mechanism for the transition of R~*·G_tαβγ·GDP to the nucleotide-free R~*·G protein complex that illustrates how a5 might act as a transmission rod to propagate the conformational change from the receptor-G protein interface to the nucleotide binding site.
机译：细胞外信号促使G蛋白偶联受体（GPCR）采取主动构象（R〜*），并催化细胞内G蛋白（Gaβγ）的α亚基中的GDP / GTP交换。对转导蛋白（G_tαβγ）活化的动力学分析表明，在GDP释放和无核苷酸的R〜·G蛋白复合物形成之前，形成了中间的R〜*·G_tαβγGDP复合物。基于此反应序列，我们探索了这些复合物形成过程中蛋白质之间的动态界面。我们从由GPCR视蛋白的晶体结构获得的G_tαC末端肽（GαCT）稳定的R〜*构象开始。分子建模可以重建G_tα（α5）的完全伸长的C端α螺旋，并显示如何将α5停靠到R〜*的开放结合位点。找到了两种交互方式。其中之一被称为稳定或S相互作用，与GαCT肽在晶体结构中的位置匹配，并在GαCT的C端反向转角与保守的E（D）RY和NPxxY（x）之间复制氢键网络。 -GPCR的_（5.6）F区。替代拟合-称为中介或l交互-通过a5相对于S交互的倾斜（42°）和旋转（90°）来区分，并显示与NPxxY（x）_（5.6）F的不同α5接触区域和R〜*的第二个胞质环。从2α5相互作用中，我们得出了R〜*·G_tαβγ·GDP向无核苷酸的R〜*·G蛋白复合物过渡的“螺旋开关”机制，该机理说明了a5可能如何充当传播构象的传递棒。从受体-G蛋白界面改变到核苷酸结合位点。

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    Patrick Scheerer; Martin Heck; Andrean Goede; Jung Hee Park; Hui-Woog Choe; Oliver P. Ernst; Klaus Peter Hofmann; Peter W. Hildebrand;

  • 作者单位

    Institut fuer Medizinische Physik und Biophysik (CC2), Charite-Universitaetsmedizin Berlin, D-10117 Berlin, Germany;

    Institut fuer Medizinische Physik und Biophysik (CC2), Charite-Universitaetsmedizin Berlin, D-10117 Berlin, Germany;

    Institut fuer Biochemie, Charite-Universitaetsmedizin Berlin, D-10117 Berlin, Germany;

    Institut fuer Medizinische Physik und Biophysik (CC2), Charite-Universitaetsmedizin Berlin, D-10117 Berlin, Germany;

    Institut fuer Medizinische Physik und Biophysik (CC2), Charite-Universitaetsmedizin Berlin, D-10117 Berlin, Germany Department of Chemistry, College of Natural Science, Chonbuk National University, 561-756 Chonju, South Korea;

    Institut fuer Medizinische Physik und Biophysik (CC2), Charite-Universitaetsmedizin Berlin, D-10117 Berlin, Germany;

    Institut fuer Medizinische Physik und Biophysik (CC2), Charite-Universitaetsmedizin Berlin, D-10117 Berlin, Germany Zentrum fuer Biophysik und Bioinformatik, Humboldt-Universitaet zu Berlin, Invalidenstrasse 42, D-10115 Berlin, Germany;

    Institut fuer Medizinische Physik und Biophysik (CC2), Charite-Universitaetsmedizin Berlin, D-10117 Berlin, Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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  • 关键词

    protein complex; G protein; G protein coupled receptor signal transduction; protein-protein interaction;

    机译：蛋白质复合物G蛋白;G蛋白偶联受体信号转导;蛋白质相互作用;

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