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首页> 外文期刊>Biochemistry >Determinants of Ligand Binding Affinity and Cooperativity at the GLUT1 Endofacial Site
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Determinants of Ligand Binding Affinity and Cooperativity at the GLUT1 Endofacial Site

机译：配体结合亲和力和合作性在GLUT1面部的决定因素。

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摘要

Cytochalasin B (CB) and forskolin (FSK)ninhibit GLUT1-mediated sugar transport in red cells by bindingnat or close to the GLUT1 endofacial sugar binding site.nParadoxically, very low concentrations of each of these inhibi-ntors produce a modest stimulation of sugar transport [Cloherty,nE. K., Levine, K. B., and Carruthers, A. (2001) The red blood cell glucose transporter presents multiple, nucleotide-sensitive sugarnexit sites. Biochemistry 40 (51), 15549 15561]. This result is consistent with the hypothesis that the glucose transporter containsnmultiple, interacting, endofacial binding sites for CB and FSK. The present study tests this hypothesis directly and, by screening anlibrary of cytochalasin and forskolin analogues, asks what structural features of endofacial site ligands determine binding site affinitynand cooperativity. Like CB, FSK competitively inhibits exchange 3-O-methylglucose transport (sugar uptake in cells containingnintracellular sugar) but noncompetitively inhibits sugar uptake into cells lacking sugar at 4 u0001C. This refutes the hypothesis that FSKnbinds at GLUT1 endofacial and exofacial sugar binding sites. Some forskolin derivatives and cytochalasins inhibit equilibrium [n3nH]-nCB binding to red cell membranes depleted of peripheral proteins at 4 u0001C. Others produce a moderate stimulation of [n3nH]-CBnbinding when introduced at low concentrations but inhibit binding as their concentration is increased. Yet other analoguesmodestlynstimulate [n3nH]-CB binding at all inhibitor concentrations applied. These findings are explained by a carrier that presents at least twoninteracting endofacial binding sites for CB or FSK. We discuss this result within the context of models for GLUT1-mediated sugarntransport and GLUT1 quaternary structure, and we evaluate the major determinants of ligand binding affinity and cooperativity.
机译：细胞松弛素B（CB）和毛喉素（FSK）通过结合或接近GLUT1界面糖结合位点抑制红细胞中GLUT1介导的糖转运。矛盾的是，每种抑制剂的极低浓度都会适度刺激糖转运[Cloherty，NE。 K.，Levine，K.B。和Carruthers，A。（2001），红细胞葡萄糖转运蛋白具有多个核苷酸敏感的糖脱位点。生物化学40（51），15549 15561]。该结果与葡萄糖转运蛋白包含多个CB和FSK的相互作用的界面结合位点的假设相一致。本研究直接检验了这一假设，并通过筛选细胞松弛素和毛喉素类似物的库，询问界面位点配体的哪些结构特征决定了结合位点的亲和力和协同性。像CB一样，FSK竞争性地抑制交换3-O-甲基葡萄糖转运（在含胞内糖的细胞中摄取糖分），但在4 u0001C时非竞争性地抑制糖缺乏的细胞摄取糖分。这驳斥了FSKnbinds在GLUT1面内和面外糖结合位点的假设。一些毛喉素衍生物和细胞松弛素在4 u0001C处抑制平衡的[n3nH] -nCB与耗尽外围蛋白的红细胞膜的结合。当其他化合物以低浓度引入时，它们会产生对[n3nH] -CBn结合的中等刺激，但随着其浓度的增加而抑制结合。在施加的所有抑制剂浓度下，其他类似物也会适度刺激[n3nH] -CB结合。这些发现是由一种载体解释的，该载体至少具有两个相互作用的CB或FSK界面结合位点。我们在GLUT1介导的糖转运和GLUT1季结构模型的背景下讨论了这一结果，并评估了配体结合亲和力和协同作用的主要决定因素。

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