Brooks Benjamin E, Piro Kevin M, Brennan Richard G
Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Unit 1000, Houston, TX 77030, USA.
J Am Chem Soc. 2007 Jul 4;129(26):8389-95. doi: 10.1021/ja072576v. Epub 2007 Jun 13.
Staphylococcus aureus QacR is a multidrug-binding transcription repressor. Crystal structures of multiple QacR-drug complexes reveal that these toxins bind in a large pocket, which is composed of smaller overlapping "minipockets". Stacking, van der Waals, and ionic interactions are common features of binding, whereas hydrogen bonds are limited. Pentamidine, a bivalent aromatic diamidine, interacts with QacR differently as one positively charged benzamidine moiety is neutralized by the dipoles of side-chain and peptide backbone oxygens rather than a formal negative charge from proximal acidic residues. To understand the binding mechanisms of other bivalent benzamidines, we determined the crystal structures of the QacR-DB75 and QacR-DB359 complexes and measured their binding affinities. Although these rigid aromatic diamidines bind with low-micromolar affinities, they do not use single, discrete binding modes. Such promiscuous binding underscores the intrinsic chemical redundancy of the QacR multidrug-binding pocket. Chemical redundancy is likely a hallmark of all multidrug-binding pockets, yet it is utilized by only a subset of drugs, which, for QacR, so far appears to be limited to chemically rigid, bivalent compounds.
金黄色葡萄球菌QacR是一种多药结合转录阻遏物。多个QacR-药物复合物的晶体结构表明，这些毒素结合在一个大口袋中，该口袋由较小的重叠“微口袋”组成。堆积、范德华力和离子相互作用是结合的常见特征，而氢键则较为有限。喷他脒是一种二价芳香族二脒，与QacR的相互作用方式不同，因为一个带正电荷的苯甲脒部分被侧链和肽主链氧的偶极中和，而不是来自近端酸性残基的形式负电荷。为了了解其他二价苯甲脒的结合机制，我们测定了QacR-DB75和QacR-DB359复合物的晶体结构并测量了它们的结合亲和力。尽管这些刚性芳香族二脒以低微摩尔亲和力结合，但它们并不采用单一、离散的结合模式。这种混杂结合突出了QacR多药结合口袋的内在化学冗余性。化学冗余可能是所有多药结合口袋的一个标志，但只有一部分药物利用了它，对于QacR来说，到目前为止似乎仅限于化学刚性的二价化合物。
