HEMOGLOBIN - STRUCTURAL-CHANGES RELATED TO LIGAND-BINDING AND ITS ALLOSTERIC MECHANISM
HEMOGLOBIN - STRUCTURAL-CHANGES RELATED TO LIGAND-BINDING AND ITS ALLOSTERIC MECHANISM
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DOI：
10.1016/0022-2836(79)90277-8
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发表时间：
1979-01-01
影响因子：
5.6
通讯作者：
CHOTHIA, C
中科院分区：
文献类型：
--
作者：
BALDWIN, J;CHOTHIA, C
利用计算机图形学和最小二乘拟合方法，比较了人脱氧、马胺和人羰基血红蛋白的原子坐标，研究了配体与血红蛋白结合时的结构变化。从脱氧到任何一种配体形式所发生的变化是非常相似的。这些变化包括.alpha.1.beta中的三级结构变化。二聚体和四元结构发生变化，其中填料为。α。1对。alpha。2。beta。2改变。在从脱氧到配体Hb的过程中，α .1. β的中心区域没有发生明显的结构变化。1二聚体，包括。α。1。在两个亚基中都有1个界面和附近的螺旋B、C、G和H。运动发生在二聚体的外部部分，其中两个亚基的血红素，F螺旋和FG角向分子中心移动。2血红素角和2 FG角。2 .ANG。走得更近。两个亚基变化的一个重要影响是将F螺旋通过血红素表面翻译。apprx。1 .ANG . .这使得血红素连接的组氨酸F8从脱氧中与卟啉氮不对称的位置移动到配体Hb中更对称的位置。的运动。血红素从val . β附近去除配体结合位点。E11，在脱氧中阻碍配体结合。三级结构的变化通过FG角的运动与四级结构的变化联系在一起。α。1。β的C螺旋和FG角。1 .与。alpha.2.beta的FG角和C螺旋接触。在两个四元结构中都有。在四元变换中。1FG和。2C和。之间。2FG和。1C作为灵活的关节，允许小的相对运动。在两种结构中，相同的侧链参与了接触。与。alpha。1C和。β。2FG和。之间。2C和。1FG作为开关区域，有两个不同的稳定位置，不同的侧链接触。两个位置之间的变化涉及.apprx的相对移动。6 .ANG . .四元结构改变为配体Hb破坏了脱氧Hb中每个亚基的c端残基所形成的接触，这些残基在配体形式下自由旋转。这些结构结果，连同其他工作，特别是Gelin和Karplus以及Warshel的计算，支持Hb机制的描述，其中配体与脱氧形式的结合伴随着空间应变，源于F螺旋和HisF8相对于血红素的特定位置。应变导致脱氧四元结构相对于配体四元结构的稳定性降低，因此随着配体的结合，高亲和形式的分子比例增加。四级结构转变为高亲和形式引起三级结构变化，使F螺旋和HisF8相对于血红素重新定位，然后配体结合没有应变。在没有配体的情况下，在。α。1. β之间埋藏的较大表面积有利于脱氧结构。1和。alpha。2。beta。在这个四元结构中。讨论了结构结果的进一步含义。
The structural changes that occur on ligand binding to Hb were studied by comparison of the atomic coordinates of human deoxy, horse met and human carbonmonoxy Hb, using computer graphics and least-squares fitting methods. The changes that occur on going from deoxy to either of the liganded forms are very similar. These include tertiary structure changes within the .alpha.1.beta.1 dimer and a quaternary structure change in which the packing of .alpha.1.beta.1 against .alpha.2.beta.2 alters. On going from deoxy to liganded Hb, no significant structural change occurs in the central regions of the .alpha.1.beta.1 dimer, including the .alpha.1.beta.1 interface and nearby helices B, C, G and H in both subunits. Movements occur in the outer parts of the dimer, where the heme, F helices and FG corners of both subunits move towards the center of the molecule. The 2 heme and the 2 FG corners come .apprx. 2 .ANG. closer together. One important effect of the changes in both subunits is to translate the F helix across the face of the heme by .apprx. 1 .ANG.. This moves the heme-linked histidine F8 from a position that is asymmetric with respect to the porphyrin nitrogens in deoxy to a more symmetric position in liganded Hb. The motion of the .beta. heme removes the ligand-binding site from the vicinity of Val.beta.E11, which hinders ligand binding in deoxy. The changes in tertiary structure are linked to the quaternary change through the motion of the FG corners. The C helices and FG corners of .alpha.1.beta.1 are in contact with the FG corners and C helices of .alpha.2.beta.2 in both quaternary structures. In the quaternary change the contacts between .alpha.1FG and .beta.2C and between .alpha.2FG and .beta.1C act as flexible joints allowing small relative motions. The same side-chains are involved in the contacts in both structures. The contacts between .alpha.1C and .beta.2FG and between .alpha.2C and .beta.1FG act as switch regions, having 2 different stable positions with different side-chains in contact. The change between the 2 positions involves a relative movement of .apprx. 6 .ANG.. The quaternary structure change to liganded Hb destroys the contacts made by the C-terminal residues of each subunit in deoxy Hb, and these residues rotate freely in the liganded form. These structural results, together with other work, particularly the calculations of Gelin and Karplus and of Warshel, support a description of the Hb mechanism in which the binding of ligand to the deoxy form is accompanied by steric strain, originating from the particular position of the F helix and of HisF8 relative to the heme. The strain leads to decreased stability of the deoxy quaternary structure relative to the liganded quaternary structure, so that the proportion of molecules in the high-affinity form increases as successive ligands bind. The quaternary structure change to the high-affinity form induces tertiary structure changes that reposition the F helix and HisF8 relative to the heme and there is then no strain on ligand binding. In the absence of ligand the deoxy structure is favored by the greater surface area buried between .alpha.1.beta.1 and .alpha.2.beta.2 in this quaternary structure. Further implications of the structural results were discussed.