ALLOSTERIC MODIFIERS OF HEMOGLOBIN .2. CRYSTALLOGRAPHICALLY DETERMINED BINDING-SITES AND HYDROPHOBIC BINDING INTERACTION ANALYSIS OF NOVEL HEMOGLOBIN OXYGEN EFFECTORS
ALLOSTERIC MODIFIERS OF HEMOGLOBIN .2. CRYSTALLOGRAPHICALLY DETERMINED BINDING-SITES AND HYDROPHOBIC BINDING INTERACTION ANALYSIS OF NOVEL HEMOGLOBIN OXYGEN EFFECTORS
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DOI：
10.1021/jm00106a042
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发表时间：
1991-02-01
影响因子：
7.3
通讯作者：
ABRAHAM, DJ
中科院分区：
文献类型：
--
作者：
WIREKO, FC;KELLOGG, GE;ABRAHAM, DJ
用x射线晶体学测定了六种类似贝扎贝特的新型变构效应物的蛋白结合构象，它们显著降低了血红蛋白的氧亲和力。与Lalezari， Perutz和同事报道的三种尿素类似物的结合构象进行了比较。所有六个新分子都在先前观察到的贝扎布酸的同一位点结合，并表现出广泛的变构活性。尿素衍生物最有效的衍生物具有两个结合位点，而六个新分子中只有一个（具有中等变构活性的）具有第二个结合位点。一个新的计算机程序，HINT（疏水相互作用），已经被创建并用于识别小分子和蛋白质之间的主要相互作用。通过HINT鉴定出的最强的3种相互作用分别是Arg 141- α与类似物的酸、Lys 99- α与桥接酰胺羰基、Asn 108- β侧链的酰胺NH与卤化芳环。
The protein-bound conformations of six new allosteric effectors similar to bezafibrate that markedly decrease the oxygen affinity of hemoglobin have been determined by X-ray crystallography. Comparisons are made with the bound conformations of three urea analogues reported by Lalezari, Perutz, and co-workers. All six new molecules bind at the same site previously observed for bezafibrate and exhibit a wide range of allosteric activity. Unlike the urea derivatives, which show two binding sites for the most potent derivatives, only one of the six new molecules (one with moderate allosteric activity) exhibits a second binding site. A new computer program, HINT (hydrophobic interactions), has been created and utilized to identify the major interactions between small molecules and the protein. The three strongest interactions identified by HINT involve Arg 141-alpha with the acid of the analogues, Lys 99-alpha with the bridging amide carbonyl, and the amide NH of the side chain of Asn 108-beta with the halogenated aromatic ring.