Mechanism of inhibition of human glucose transporter GLUT1 is conserved between cytochalasin B and phenylalanine amides
Mechanism of inhibition of human glucose transporter GLUT1 is conserved between cytochalasin B and phenylalanine amides
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DOI：
10.1073/pnas.1603735113
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发表时间：
2016-04-26
影响因子：
11.1
通讯作者：
Stroud, Robert M.
中科院分区：
文献类型：
--
作者：
Kapoor, Khyati;Finer-Moore, Janet S.;Stroud, Robert M.
癌细胞对能量的需求急剧增加，导致人类葡萄糖转运蛋白 1 (hGLUT1) 水平增加。这种上调表明 hGLUT1 作为治疗多种癌症类型的抑制剂的靶点。在这里，我们提出了三种抑制剂结合的、向内开放的 WT-hGLUT1 结构，用三种不同的抑制剂结晶：细胞松弛素 B，与 14 元大环融合的九元双环，在 hGLUT 文献中已广泛描述，以及两种先前未描述的 Phe 酰胺衍生抑制剂。尽管化学主链非常不同，但所有三种化合物都结合在 hGLUT1 向内开放状态的中央腔中，并且所有结合位点都与葡萄糖结合位点重叠。使用基于细胞的测定法确定了化合物对 hGLUT 家族成员 hGLUT1-4 的抑制作用，并与这些 hGLUT 成员的同源模型进行了比较。这一比较揭示了观察到的家庭成员之间抑制差异的可能基础。我们查明了 hGLUT 蛋白的可靶向区域以实现异构体选择性，并表明这些相同区域可用于具有非常独特的结构主链的抑制剂。 hGLUT1 的抑制剂复合物结构为设计更具选择性的 hGLUT，特别是 hGLUT1 抑制剂提供了重要的结构见解。
Cancerous cells have an acutely increased demand for energy, leading to increased levels of human glucose transporter 1 (hGLUT1). This up-regulation suggests hGLUT1 as a target for therapeutic inhibitors addressing a multitude of cancer types. Here, we present three inhibitor-bound, inward-open structures of WT-hGLUT1 crystallized with three different inhibitors: cytochalasin B, a nine-membered bicyclic ring fused to a 14-membered macrocycle, which has been described extensively in the literature of hGLUTs, and two previously undescribed Phe amide-derived inhibitors. Despite very different chemical backbones, all three compounds bind in the central cavity of the inward-open state of hGLUT1, and all binding sites overlap the glucose-binding site. The inhibitory action of the compounds was determined for hGLUT family members, hGLUT1-4, using cell-based assays, and compared with homology models for these hGLUT members. This comparison uncovered a probable basis for the observed differences in inhibition between family members. We pinpoint regions of the hGLUT proteins that can be targeted to achieve isoform selectivity, and show that these same regions are used for inhibitors with very distinct structural backbones. The inhibitor cocomplex structures of hGLUT1 provide an important structural insight for the design of more selective inhibitors for hGLUTs and hGLUT1 in particular.