6HWM

Structure of Thermus thermophilus ClpP in complex with bortezomib

Summary for 6HWM

• Entry DOI: 10.2210/pdb6hwm/pdb
• Descriptor: ATP-dependent Clp protease proteolytic subunit, N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL)-L-PHENYLALANINAMIDE, DI(HYDROXYETHYL)ETHER (3 entities in total)
• Functional Keywords: hydrolase, complex, activator
• Biological source: Thermus thermophilus
• Total number of polymer chains: 7
• Total formula weight: 162349.75

Authors

Felix, J.,Schanda, P.,Fraga, H.,Morlot, C. (deposition date: 2018-10-12, release date: 2019-09-18, Last modification date: 2024-10-09)

Primary citation

Felix, J.,Weinhaupl, K.,Chipot, C.,Dehez, F.,Hessel, A.,Gauto, D.F.,Morlot, C.,Abian, O.,Gutsche, I.,Velazquez-Campoy, A.,Schanda, P.,Fraga, H.
Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors.
Sci Adv, 5:eaaw3818-eaaw3818, 2019

PubMed Abstract: Coordinated conformational transitions in oligomeric enzymatic complexes modulate function in response to substrates and play a crucial role in enzyme inhibition and activation. Caseinolytic protease (ClpP) is a tetradecameric complex, which has emerged as a drug target against multiple pathogenic bacteria. Activation of different ClpPs by inhibitors has been independently reported from drug development efforts, but no rationale for inhibitor-induced activation has been hitherto proposed. Using an integrated approach that includes x-ray crystallography, solid- and solution-state nuclear magnetic resonance, molecular dynamics simulations, and isothermal titration calorimetry, we show that the proteasome inhibitor bortezomib binds to the ClpP active-site serine, mimicking a peptide substrate, and induces a concerted allosteric activation of the complex. The bortezomib-activated conformation also exhibits a higher affinity for its cognate unfoldase ClpX. We propose a universal allosteric mechanism, where substrate binding to a single subunit locks ClpP into an active conformation optimized for chaperone association and protein processive degradation.

PubMed: 31517045
DOI: 10.1126/sciadv.aaw3818

Experimental method

X-RAY DIFFRACTION (2.7 Å)