解决方案的结构和骨架动态pleckstrin同源域的人类蛋白激酶B (PKB / Akt)。与肌醇磷酸盐的交互。
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Auguin D, Barthe P, Auge-Senegas MT,斯特恩MH,野口M, Roumestand C
解决方案的结构和骨架动态pleckstrin同源域的人类蛋白激酶B (PKB / Akt)。与肌醇磷酸盐的交互。
J Biomol NMR。2004年2月,28 (2):137 - 55。
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14755158 (在PubMed]
- 文摘
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程序性细胞死亡发生作为哺乳动物的正常发展的一部分。发展的感应细胞死亡是一个高度管制的过程,可以抑制由多种细胞外刺激。最近,营养因素促进生存的能力一直认为,至少在某种程度上,phosphatidylinositide 3 '羟基激酶(PI3K) /蛋白激酶B (PKB也叫Akt)级联。PI3K / PKB的几个目标信号通路的能力已确定,可能这个监管级联促进细胞的生存。PKB具有氨基端Pleckstrin同源性(PH)域,结合具体和具有高亲和力PtIns (3、4、5) P(3)和PtIns (3, 4) P (2), PI3K第二信使。PKB随后被招募到质膜由于其与3 ' -哦phosphatidylinositides和激活。最近的证据表明,PKB活跃在各种类型的人类癌症;本构PKB信号的激活被认为促进增殖和增加细胞生存,从而导致癌症的发展。因此,它已经表明,感应TCL1 / PKB活性增强的MTCP1癌基因蛋白通过物理协会要求PKB PH域。我们现在的PH值的三维解决方案结构域的人类蛋白质PKB(同种型β)。 PKBbeta-PH is an electrostatically polarized molecule that adopts the same fold and topology as other PH-domains, consisting of a beta-sandwich of seven strands capped on one top by an alpha-helix. The opposite face presents three variable loops that appear poorly defined in the NMR structure. Measurements of (15)N spin relaxation times and heteronuclear (15)N[(1)H]NOEs showed that this poor definition is due to intrinsic flexibility, involving complex motions on different time scales. Chemical shift mapping studies correctly defined the binding site of Ins(1,3,4,5)P(4) (the head group of PtIns(3,4,5)P(3)), as was previously proposed from a crystallographic study. More interestingly, these studies allowed us to define a putative alternative low-affinity binding site for Ins(1,4,5)P(3). The binding of this sugar to PKBbeta-PH might also involve non-specific association that could explain the stabilization of the protein in solution in the presence of Ins(1,4,5)P(3).