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[摘要]：Via high-throughput screening of a natural compound library, we have identified a lipopeptide aldehyde, fellutamide B (1), as the most potent inhibitor of the Mycobacterium tuberculosis (Mtb) proteasome tested to date Kinetic studies reveal that 1 inhibits both Mtb and human proteasomes in a time-dependent manner under steady-state condition Remarkably, 1 inhibits the Mtb proteasome in a single-step binding mechanism with K-1 = 68 nM, whereas it inhibits the human proteasome beta 5 active site following a two-step mechanism with K-1 = 11 5 nM and K-1 = 0.93 nM Co-crystallization of 1 bound to the Mtb proteasome revealed a structural basis for the tight binding of 1 to the active sites of the Mtb proteasome The hemiacetal group of 1 in the Mtb proteasome takes the (R)-configuration, whereas in the yeast proteasome it takes the (S)-configuration, indicating that the pre-chiral CHO group of 1 binds to the active site Thr1 in a different orientation Re-examination of the structure of the yeast proteasome in complex with 1 showed significant conformational changes at the substrate-binding cleft along the active site These structural differences are consistent with the different kinetic mechanisms of 1 against Mtb and human proteasomes (C) 2010 Elsevier Inc All rights reserved |
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