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1szm

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{{STRUCTURE_1szm| PDB=1szm | SCENE= }}
{{STRUCTURE_1szm| PDB=1szm | SCENE= }}
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'''DUAL BINDING MODE OF BISINDOLYLMALEIMIDE 2 TO PROTEIN KINASE A (PKA)'''
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===DUAL BINDING MODE OF BISINDOLYLMALEIMIDE 2 TO PROTEIN KINASE A (PKA)===
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==Overview==
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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.
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(as it appears on PubMed at http://www.pubmed.gov), where 14996846 is the PubMed ID number.
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{{ABSTRACT_PUBMED_14996846}}
==About this Structure==
==About this Structure==
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==Reference==
==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:[http://www.ncbi.nlm.nih.gov/pubmed/14996846 14996846]
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:[http://www.ncbi.nlm.nih.gov/pubmed/14996846 14996846]
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Staurosporine-induced conformational changes of cAMP-dependent protein kinase catalytic subunit explain inhibitory potential., Prade L, Engh RA, Girod A, Kinzel V, Huber R, Bossemeyer D, Structure. 1997 Dec 15;5(12):1627-37. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9438863 9438863]
[[Category: Bos taurus]]
[[Category: Bos taurus]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Surrogate kinase]]
[[Category: Surrogate kinase]]
[[Category: X-ray structure]]
[[Category: X-ray structure]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 09:19:05 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 15:34:54 2008''

Revision as of 12:35, 28 July 2008

Image:1szm.png

Template:STRUCTURE 1szm

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

Template:ABSTRACT PUBMED 14996846

About this Structure

1SZM is a Single protein structure of sequence from Bos taurus. 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

Staurosporine-induced conformational changes of cAMP-dependent protein kinase catalytic subunit explain inhibitory potential., Prade L, Engh RA, Girod A, Kinzel V, Huber R, Bossemeyer D, Structure. 1997 Dec 15;5(12):1627-37. PMID:9438863

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