Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome

Michael Groll; Celia R Berkers; Hidde L Ploegh; Huib Ovaa

doi:10.1016/j.str.2005.11.019

Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome

Structure. 2006 Mar;14(3):451-6. doi: 10.1016/j.str.2005.11.019.

Authors

Michael Groll¹, Celia R Berkers, Hidde L Ploegh, Huib Ovaa

Affiliation

¹ Department for Physiological Chemistry, Ludwig-Maximilians-University, Butenandtstrasse 5, Building B 81377, München, Germany. mgroll@med.uni-muenchen.de

PMID: 16531229
DOI: 10.1016/j.str.2005.11.019

Abstract

The dipeptide boronic acid bortezomib, also termed VELCADE, is a proteasome inhibitor now in use for the treatment of multiple myeloma, and its use for the treatment of other malignancies is being explored. We determined the crystal structure of the yeast 20S proteasome in complex with bortezomib to establish the specificity and binding mode of bortezomib to the proteasome's different catalytically active sites. This structure should enable the rational design of new boronic acid derivatives with improved affinities and specificities for individual active subunits.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemistry
Boronic Acids / chemistry*
Bortezomib
Catalytic Domain
Crystallization
Leucine
Mammals / genetics
Models, Molecular
Peptides
Phenylalanine
Proteasome Endopeptidase Complex / chemistry*
Protein Structure, Quaternary
Pyrazinamide / analogs & derivatives
Pyrazinamide / chemistry
Pyrazines / chemistry*
Structure-Activity Relationship
Substrate Specificity
Yeasts / chemistry*
Yeasts / genetics

Substances

Antineoplastic Agents
Boronic Acids
Peptides
Pyrazines
Pyrazinamide
pyrazinoic acid
Phenylalanine
Bortezomib
Proteasome Endopeptidase Complex
Leucine

Associated data

PDB/2F16