Kahmann Jan D, Sass Hans-Jürgen, Allan Martin G, Seto Haruo, Thompson Charles J, Grzesiek Stephan
Division of Structural Biology, Biozentrum der Universität Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland.
EMBO J. 2003 Apr 15;22(8):1824-34. doi: 10.1093/emboj/cdg181.
The TipAL protein, a bacterial transcriptional regulator of the MerR family, is activated by numerous cyclic thiopeptide antibiotics. Its C-terminal drug-binding domain, TipAS, defines a subfamily of broadly distributed bacterial proteins including Mta, a central regulator of multidrug resistance in Bacillus subtilis. The structure of apo TipAS, solved by solution NMR [Brookhaven Protein Data Bank entry 1NY9], is composed of a globin-like alpha-helical fold with a deep surface cleft and an unfolded N-terminal region. Antibiotics bind within the cleft at a position that is close to the corresponding heme pocket in myo- and hemoglobin, and induce folding of the N-terminus. Thus the classical globin fold is well adapted not only for accommodating its canonical cofactors, heme and other tetrapyrroles, but also for the recognition of a variety of antibiotics where ligand binding leads to transcriptional activation and drug resistance.
TipAL蛋白是MerR家族的一种细菌转录调节因子，可被多种环肽抗生素激活。其C端药物结合结构域TipAS定义了一类广泛分布的细菌蛋白亚家族，包括枯草芽孢杆菌多药耐药性的核心调节因子Mta。通过溶液核磁共振解析的无配体TipAS结构（布鲁克海文蛋白质数据库条目1NY9）由一个具有深表面裂隙的类球蛋白α螺旋折叠和一个未折叠的N端区域组成。抗生素在裂隙内靠近肌红蛋白和血红蛋白中相应血红素口袋的位置结合，并诱导N端折叠。因此，经典的球蛋白折叠不仅非常适合容纳其典型辅因子血红素和其他四吡咯，还适合识别多种抗生素，其中配体结合会导致转录激活和耐药性。
