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Enzymatic mechanisms of Staphylococcus aureus Clp Protease
Update time: 2013-07-15
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The ATP-dependent Clp protease (ClpP), which consists of two heptameric rings that enclose a large chamber, plays an essential role not only in the control of protein quality but also in the regulation of bacterial pathogen virulence, making it an attractive target for antibacterial treatment. However, there are no agents under clinical trial targeting ClpP reported at present.

The research team of antibacterial study in Shanghai Institute of Materia Medica has made a great breakthrough in understanding molecular mechanisms of ClpP from Staphylococcus aureus (SaClpP).

In this study, doctoral students YE Fei and ZHANG Jie, led by Professor LUO Cheng and YANG Caiguang, demonstrated the enzymatic dynamics and acting mechanisms of ClpP based on the crystal structures of SaClpP in two different states they have previously determined, extended and compressed. Guided by MD simulations, they investigate the pathway and mechanism of SaClpP between different states.

As a stable intermediate in the MD simulation, the compact state was suggested and subsequently identified in X-ray crystallographic study. Based on MD simulation, they also predicted several crucial residues during conformational change, e.g. E137, A140, which were validated by mutation experiments. Overall, the MD simulations, along with X-ray structural analysis, provided new insights into the mechanism of the dynamic switching of SaClpP.

After degradation of substrate peptides, accumulation and release of digested fragments from the active site may induce a rearrangement of the catalytic triad, thereby leading to the destruction of the nearby R171_D170 contact network. As a result, the extended ClpP transforms into the compressed state, which is stabilized by E137 network. During the conformational transition, the long and straight helix E in the extended state undergoes an unfolding/refolding process during the conformational transition, resulting in a kinked conformation very similar to what was observed in the compressed state. A140 acts as a “hinge” in the conformational changes of helix E.

Given the highly conserved sequences of ClpP proteins among different species, these findings potentially reflect a switching mechanism for the dynamic process shared in the whole ClpP family in general, and also aid in designing new anti-infective agents.

Based on previous study (J Biol Chem, 2011, 286, 37590-601), research team published this paper in the Journal of Biological Chemistry (J Biol Chem, 2013, 288, 17643–53).

This study was supported by Shanghai Institute of Materia Medica, National Natural Science Foundation of China and National High Technology Research and Development Program of China Grant. The computation resources were supported by Computation resources provided by the Computer Network Information Center, Chinese Academy of Sciences, Tianjin Super-computing Center and Shanghai Supercomputing Center.

Paper link: 

Three states of ClpP and key residues in the functional cycle

(News Source: JIANG Hualiang's  group)
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