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Probing structural determinants distal to the site of hydrolysis that control substrate specificity of the 20S proteasome

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons78033

Groll,  M.
Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78142

Huber,  R.
Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Groll, M., Nazif, T., Huber, R., & Bogyo, M. (2002). Probing structural determinants distal to the site of hydrolysis that control substrate specificity of the 20S proteasome. Chemistry & Biology, 9(5), 655-662.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0010-6F50-1
Abstract
The 20S proteasome is a large multicomponent protease complex. Relatively little is known about the mechanisms that control substrate specificity of its multiple active sites. We present here the crystal structure at 2.95 Angstrom resolution of a beta2-selective inhibitor (MB1) bound to the yeast 20S proteasome core particle (CP). This structure is compared to the structure of the CP bound to a general inhibitor (MB2) that covalently modified all three (beta1, beta2, beta5) catalytic subunits. These two inhibitors differ only in their P3 and P4 residues, thereby highlighting binding interactions distal to the active site threonine that control absolute substrate specificity of the complex. Comparisons of the CP-bound structures of MB1, MB2, and the natural products epoxomycin and TMC-95A also provide information regarding general binding modes for several classes of proteasome inhibitors.