3KRD

Crystal Structure of Mycobacterium Tuberculosis Proteasome in complex with Fellutamide B

Summary for 3KRD

• Entry DOI: 10.2210/pdb3krd/pdb
• Related: 2FHG 2FHH 3H6F 3H6I 3HF9 3HFA
• Descriptor: Proteasome subunit alpha, Proteasome subunit beta, Fellutamide B, ... (5 entities in total)
• Functional Keywords: binding sites, mycobacterium tuberculosis, protein subunits, substrate specificity, hydrolase, proteasome, fellutamide b, inhibition, protease, threonine protease, virulence, autocatalytic cleavage, zymogen
• Biological source: Mycobacterium tuberculosis; More
• Cellular location: Cytoplasm (By similarity): A5U4D5 A5U4D6
• Total number of polymer chains: 42
• Total formula weight: 738850.35

Authors

Li, D.,Li, H. (deposition date: 2009-11-18, release date: 2010-09-29, Last modification date: 2024-11-06)

Primary citation

Lin, G.,Li, D.,Chidawanyika, T.,Nathan, C.,Li, H.
Fellutamide B is a potent inhibitor of the Mycobacterium tuberculosis proteasome.
Arch.Biochem.Biophys., 501:214-220, 2010

PubMed Abstract: 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(i)=6.8 nM, whereas it inhibits the human proteasome beta5 active site following a two-step mechanism with K(i)=11.5 nM and K(i)(*)=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.

PubMed: 20558127
DOI: 10.1016/j.abb.2010.06.009

Experimental method

X-RAY DIFFRACTION (2.5 Å)