PDBsum entry 2f16

Hydrolase

PDB id: 2f16

Contents

Protein chains

250 a.a.

244 a.a.

241 a.a.

242 a.a.

233 a.a.

244 a.a.

243 a.a.

222 a.a.

204 a.a.

198 a.a.

212 a.a.

222 a.a.

233 a.a.

196 a.a.

Ligands

BO2 ×6

Waters ×1037

References listed in PDB file

Key reference

• Title: Crystal structure of the boronic acid-Based proteasome inhibitor bortezomib in complex with the yeast 20s proteasome.
• Authors: M.Groll, C.R.Berkers, H.L.Ploegh, H.Ovaa.
• Ref.: Structure, 2006, 14, 451-456. [DOI no: 10.1016/j.str.2005.11.019]
• PubMed id: 16531229

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.

Figure 2.
Figure 2. Critical Interactions of Bortezomib with Active Site Residues Responsible for Chymotryptic and Caspase-like Activities
Schematic overview of bortezomib bound to (A) the chymotryptic-like active site and (B) the caspase-like active site. Hydrogen bonds with correlated distances in Å are shown as brown dashed lines, whereas characteristic oxygen and nitrogen atoms are presented in red and blue capitals. The amino acid, which is responsible for the character and binding mode to the P3-pyrazine-2-carboxyl side chain of the inhibitor is located at the adjacent b-type subunit and shown in gray. The defined water molecule forming tight hydrogen bonds to the protein is depicted in magenta, and the inhibitor is shown in green.

The above figure is reprinted by permission from Cell Press: Structure (2006, 14, 451-456) copyright 2006.