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首页> 外文期刊>Acta crystallographica.Section D. Biological crystallography >Structure of fully liganded Hb ζ2β2 strapped in a tense conformation
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Structure of fully liganded Hb ζ2β2 strapped in a tense conformation

机译：完全配体结构Hbζ2β2绑在一个紧张的构象

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A variant Hb ζ2β2 s that is formed from sickle hemoglobin (Hb S; 2β2 s) by exchanging adult -globin with embryonic ζ-globin subunits shows promise as a therapeutic agent for sickle-cell disease (SCD). Hb ζ2β2s inhibits the polymerization of deoxygenated Hb S in vitro and reverses characteristic features of SCD in vivo in mouse models of the disorder. When compared with either Hb S or with normal human adult Hb A (2β2), Hb ζ2β2 s exhibits atypical properties that include a high oxygen affinity, reduced cooperativity, a weak Bohr effect and blunted 2,3-diphosphoglycerate allostery. Here, the 1.9514;? resolution crystal structure of human Hb ζ2β2 s that was expressed in complex transgenic knockout mice and purified from their erythrocytes is presented. When fully liganded with carbon monoxide, Hb ζ2β2 s displays a central water cavity, a ζ1-βs2 (or ζ2-βs1) interface, intersubunit salt-bridge/hydrogen-bond interactions, C-terminal βHis146 salt-bridge interactions, and a β-cleft, that are highly unusual for a relaxed hemoglobin structure and are more typical of a tense conformation. These quaternary tense-like features contrast with the tertiary relaxed-like conformations of the ζ1βs1 dimer and the CD and FG corners, as well as the overall structures of the heme cavities. This crystallographic study provides insights into the altered oxygen-transport properties of Hb ζ2β2 s and, moreover, decouples tertiary- and quaternary-structural events that are critical to Hb ligand binding and allosteric function.
机译：Hbζ变体2β2 s由镰状血红蛋白(Hb年代;球蛋白与胚胎ζ球蛋白子单元显示承诺为镰状细胞治疗代理疾病(SCD)。缺氧Hb体外和聚合逆转SCD体内的特征在小鼠模型的障碍。与Hb年代或与正常成人乙肝(2β2),Hbζ2β2 s展品典型属性包括氧亲和力高,减少了协同,玻尔效应弱和钝化2, 3-diphosphoglycerate变构效应。1.9514; ?ζ2β2 s,在复杂的转基因表达从他们的基因敲除小鼠和纯化红细胞。与一氧化碳、Hbζ2β2 s显示中央水腔,ζ1 -βs2(或ζ2 -βs1)接口,intersubunit盐桥/形成氢键交互,c端βHis146盐桥交互和β裂,这是高度血红蛋白结构和不同寻常的放松更典型的紧张的构象。与第四纪紧张得像特性三级relaxed-likeζ1βs1的构象二聚体和CD FG角落,以及血红素的整体结构蛀牙。晶体研究提供了见解改变氧气输送Hbζ2β2 s的属性此外,将第三,quaternary-structural至关重要的事件Hb配体结合和变构功能。

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