1szm

From Proteopedia

proteopedia linkproteopedia link

spinqualitylabelsall models 1szm, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

DUAL BINDING MODE OF BISINDOLYLMALEIMIDE 2 TO PROTEIN KINASE A (PKA)

Overview

As the key mediators of eukaryotic signal transduction, the protein, kinases often cause disease, and in particular cancer, when disregulated., Appropriately selective protein kinase inhibitors are sought after as, research tools and as therapeutic drugs; several have already proven, valuable in clinical use. The AGC subfamily protein kinase C (PKC) was, identified early as a cause of cancer, leading to the discovery of a, variety of PKC inhibitors. Despite its importance and early discovery, no, crystal structure for PKC has yet been reported. Therefore, we have, co-crystallized PKC inhibitor bisindolyl maleimide 2 (BIM2) with PKA, variants to study its binding interactions. BIM2 co-crystallized as an, asymmetric pair of kinase-inhibitor complexes. In this asymmetric unit, the two kinase domains have different lobe configurations, and two, different inhibitor conformers bind in different orientations. One kinase, molecule (A) is partially open with respect to the catalytic conformation, the other (B) represents the most open conformation of PKA reported so, far. In monomer A, the BIM2 inhibitor binds tightly via an induced fit in, the ATP pocket. The indole moieties are rotated out of the plane with, respect to the chemically related but planar inhibitor staurosporine. In, molecule B a different conformer of BIM2 binds in a reversed orientation, relative to the equivalent maleimide atoms in molecule A. Also, a critical, active site salt bridge is disrupted, usually indicating the induction of, an inactive conformation. Molecular modeling of the clinical phase III PKC, inhibitor LY333531 into the electron density of BIM2 reveals the probable, binding mechanism and explains selectivity properties of the inhibitor.

About this Structure

1SZM is a Single protein structure of sequence from Bos taurus with BI4 as ligand. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.

Reference

The protein kinase C inhibitor bisindolyl maleimide 2 binds with reversed orientations to different conformations of protein kinase A., Gassel M, Breitenlechner CB, Konig N, Huber R, Engh RA, Bossemeyer D, J Biol Chem. 2004 May 28;279(22):23679-90. Epub 2004 Mar 1. PMID:14996846

Page seeded by OCA on Wed Nov 21 02:52:35 2007