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首页> 外文期刊>Journal of Molecular Biology >STRUCTURAL AND FUNCTIONAL EFFECTS OF APOLAR MUTATIONS OF THE DISTAL VALINE IN MYOGLOBIN
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STRUCTURAL AND FUNCTIONAL EFFECTS OF APOLAR MUTATIONS OF THE DISTAL VALINE IN MYOGLOBIN

机译：肌球蛋白远端缬氨酸的极性突变的结构和功能作用

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摘要

High-resolution structures of the aquomet, deoxy: and CO forms of Ala68, Ile68, Leu68, and Phe68 sperm whale myoglobins have been determined by X-ray crystallography. These 12 new structures, plus those of wild-type myoglobin, have been used to interpret the effects of mutations at position 68 and the effects of cobalt substitution on the kinetics of O-2, CO, and NO binding. Molecular dynamics simulations based on crystal structures have provided information about the time-dependent behavior of photolyzed ligands for comparison with picosecond geminate recombination studies. The Val68-->Ala mutation has little effect on the structure and function of myoglobin. In Ala68 deoxymyoglobin, as in the wild-type protein, a water molecule hydrogen-bonded to the N-epsilon atom of the distal histidine restricts ligand binding and appears to be more important in regulating the function of myoglobin than direct steric interactions between the Ligand and the C-gamma atoms of the native valine side-chain. This distal pocket water molecule is displaced by the larger side-chains at position 68 in the crystal structures of Leu68 and Ile68 deoxymyoglobins. The Leu68 side-chain can rotate about its C-alpha-C-beta and C-beta-C-gamma bonds to better accommodate bound ligands, resulting in net increases in overall association rate constants and affinities due to the absence of the distal pocket water molecule. However, the flexibility of Leu68 makes simulation of picosecond NO recombination difficult since multiple starting conformations are possible. In the case of Ile68, rotation of the substituted side-chain is restricted due to branching at the beta carbon, and as a result, the delta methyl group is located close to the iron atom in both the deoxy and liganded structures. The favorable effect of displacing the distal pocket water molecule is offset by direct steric hindrance between the bound ligand and the terminal carbon atom of the isoleucine side-chain, resulting in net decreases in affinity for all three ligands and inhibition of geminate recombination which is reproduced in the molecular dynamics simulations. In Phe68 myoglobin, the benzyl side-chain is pointed away from the ligand binding site, occupying a region in the back of the distal pocket. As in wild-type and Ala68 myoglobins, a well-defined water molecule is found hydrogen bonded to the distal histidine in Phe68 deoxymyoglobin. This water molecule, in combination with the large size of the benzyl side-chain, markedly reduces the speed and extent of ligand movement into the distal pocket. Ligand movement away from the iron atom is also reduced dramatically by the Phe68 side-chain, causing large and rapid geminate recombination phases for all Ligands. [References: 53]
机译：通过X射线晶体学测定了Ala68，Ile68，Leu68和Phe68抹香鲸肌球蛋白的aquomet，脱氧和CO形式的高分辨率结构。这12个新结构，加上野生型肌红蛋白的结构，已被用来解释68位突变和钴取代对O-2，CO和NO结合动力学的影响。基于晶体结构的分子动力学模拟提供了有关光解配体随时间变化的行为的信息，可与皮秒级锗化物重组研究进行比较。 Val68-> Ala突变对肌红蛋白的结构和功能影响很小。与野生型蛋白一样，在Ala68脱氧肌红蛋白中，氢键结合到组氨酸末梢的N-ε原子上的水分子限制了配体的结合，并且在调节肌红蛋白的功能方面比配体之间的直接空间相互作用更为重要。和天然缬氨酸侧链的C-γ原子。该远端袋装水分子被Leu68和Ile68脱氧肌球蛋白的晶体结构中位置68处的较大侧链取代。 Leu68侧链可以绕其C-alpha-C-beta和C-beta-C-gamma键旋转，以更好地适应结合的配体，由于没有远端口袋，导致总缔合速率常数和亲和力的净增加水分子。但是，Leu68的灵活性使模拟皮秒NO重组变得困难，因为可能存在多个起始构象。在Ile68的情况下，由于在β碳上的分支，取代的侧链的旋转受到限制，结果，在脱氧和配体结构中，δ甲基位于靠近铁原子的位置。结合的配体和异亮氨酸侧链的末端碳原子之间的直接空间位阻抵消了置换远端袋装水分子的有利作用，从而导致对所有三个配体的亲和力净降低，并抑制了所产生的锗酸重组在分子动力学模拟中。在Phe68肌红蛋白中，苄基侧链指向远离配体结合位点的位置，占据了远端囊袋背面的区域。与野生型和Ala68肌球蛋白一样，在Phe68脱氧肌红蛋白中发现一个明确定义的水分子与远端的组氨酸氢键结合。该水分子与大尺寸的苄基侧链结合，显着降低了配体向远端囊袋移动的速度和程度。 Phe68侧链也大大减少了配体从铁原子的运动，从而导致所有配体发生大而快速的重组反应。 [参考：53]

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