Martin T W, Dauter Zbigniew, Devedjiev Yancho, Sheffield Peter, Jelen Filip, He Min, Sherman David H, Otlewski Jacek, Derewenda Zygmunt S, Derewenda Urszula
Department of Molecular Physiology and Biological Physics, University of Virginia, Health Sciences System, Charlottesville 22908, USA.
Structure. 2002 Jul;10(7):933-42. doi: 10.1016/s0969-2126(02)00778-5.
Mitomycin C (MC) is a potent anticancer agent. Streptomyces lavendulae, which produces MC, protects itself from the lethal effects of the drug by expressing several resistance proteins. One of them (MRD) binds MC and functions as a drug exporter. We report the crystal structure of MRD and its complex with an MC metabolite, 1,2-cis-1-hydroxy-2,7-diaminomitosene, at 1.5 A resolution. The drug is sandwiched by pi-stacking interactions of His-38 and Trp-108. MRD is a dimer. The betaalphabetabetabeta fold of the MRD molecule is reminiscent of methylmalonyl-CoA epimerase, bleomycin resistance proteins, glyoxalase I, and extradiol dioxygenases. The location of the binding site is identical to the ones in evolutionarily related enzymes, suggesting that the protein may have been recruited from a different metabolic pathway.
丝裂霉素C（MC）是一种强效抗癌剂。产生MC的薰衣草链霉菌通过表达几种抗性蛋白来保护自身免受该药物的致死作用。其中一种（MRD）与MC结合并作为药物外排泵发挥作用。我们报道了MRD及其与MC代谢物1,2-顺式-1-羟基-2,7-二氨基丝裂霉素的复合物在1.5埃分辨率下的晶体结构。该药物通过His-38和Trp-108的π-堆积相互作用夹在中间。MRD是一种二聚体。MRD分子的β-α-β-β折叠让人联想到甲基丙二酰辅酶A差向异构酶、博来霉素抗性蛋白、乙二醛酶I和双加氧酶。结合位点的位置与进化相关酶中的位点相同，这表明该蛋白可能是从不同的代谢途径中招募而来的。
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