Li Dominic Him Shun, Chung Yu Seon, Gloyd Melanie, Joseph Ebenezer, Ghirlando Rodolfo, Wright Gerard D, Cheng Yi-Qiang, Maurizi Michael R, Guarné Alba, Ortega Joaquin
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
Chem Biol. 2010 Sep 24;17(9):959-69. doi: 10.1016/j.chembiol.2010.07.008.
In ClpXP and ClpAP complexes, ClpA and ClpX use the energy of ATP hydrolysis to unfold proteins and translocate them into the self-compartmentalized ClpP protease. ClpP requires the ATPases to degrade folded or unfolded substrates, but binding of acyldepsipeptide antibiotics (ADEPs) to ClpP bypasses this requirement with unfolded proteins. We present the crystal structure of Escherichia coli ClpP bound to ADEP1 and report the structural changes underlying ClpP activation. ADEP1 binds in the hydrophobic groove that serves as the primary docking site for ClpP ATPases. Binding of ADEP1 locks the N-terminal loops of ClpP in a β-hairpin conformation, generating a stable pore through which extended polypeptides can be threaded. This structure serves as a model for ClpP in the holoenzyme ClpAP and ClpXP complexes and provides critical information to further develop this class of antibiotics.
在ClpXP和ClpAP复合物中，ClpA和ClpX利用ATP水解产生的能量使蛋白质解折叠，并将其转运至自我分隔的ClpP蛋白酶中。ClpP需要这些ATP酶来降解折叠或未折叠的底物，但酰基去甲肽类抗生素（ADEP）与ClpP的结合可使未折叠蛋白绕过这一需求。我们展示了与ADEP1结合的大肠杆菌ClpP的晶体结构，并报告了ClpP激活背后的结构变化。ADEP1结合在作为ClpP ATP酶主要对接位点的疏水凹槽中。ADEP1的结合将ClpP的N端环锁定在β-发夹构象中，形成一个稳定的孔道，延伸的多肽可穿过该孔道。该结构作为全酶ClpAP和ClpXP复合物中ClpP的模型，为进一步开发这类抗生素提供了关键信息。
