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首页> 外文期刊>Acta crystallographica.Section D. Biological crystallography >Structural basis for compound C inhibition of the human AMP-activated protein kinase alpha2 subunit kinase domain.
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Structural basis for compound C inhibition of the human AMP-activated protein kinase alpha2 subunit kinase domain.

机译：复合C抑制结构依据人类的活化蛋白激酶alpha2亚基激酶域。

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摘要

AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a sensor to maintain energy balance at both the cellular and the whole-body levels and is therefore a potential target for drug design against metabolic syndrome, obesity and type 2 diabetes. Here, the crystal structure of the phosphorylated-state mimic T172D mutant kinase domain from the human AMPK alpha2 subunit is reported in the apo form and in complex with a selective inhibitor, compound C. The AMPK alpha2 kinase domain exhibits a typical bilobal kinase fold and exists as a monomer in the crystal. Like the wild-type apo form, the T172D mutant apo form adopts the autoinhibited structure of the `DFG-out' conformation, with the Phe residue of the DFG motif anchored within the putative ATP-binding pocket. Compound C binding dramatically alters the conformation of the activation loop, which adopts an intermediate conformation between DFG-out and DFG-in. This induced fit forms a compound-C binding pocket composed of the N-lobe, the C-lobe and the hinge of the kinase domain. The pocket partially overlaps with the putative ATP-binding pocket. These three-dimensional structures will be useful to guide drug discovery.
机译：活化蛋白激酶(AMPK)是一个丝氨酸/苏氨酸激酶,功能传感器在维持能量平衡细胞和全身的水平因此一个潜在的药物设计的目标对代谢综合征、肥胖和2型糖尿病磷酸状态模拟T172D突变激酶域从人类AMPK alpha2亚基报道apo和在复杂的形式选择性抑制剂,化合物c AMPK alpha2一个典型的bilobal激酶激酶结构域展品褶皱和存在单体的晶体。野生型apo形式,T172D突变apo形式采用的autoinhibited结构DFG-out的构象,板式换热器残渣在假定的DFG主题的锚定磷酸腺苷的口袋里。显著的构象改变激活循环,采用一个中间构象DFG-out和DFG-in之间。诱导契合形成compound-C绑定的口袋里由N-lobe, C-lobe和铰链激酶结构域。重叠的假定的磷酸腺苷的口袋里。这些三维结构将是有用的指导药物发现。

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