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Biochemistry. 2010 May 11;49(18):3862-7. doi: 10.1021/bi100354a.

Determinants for phosphodiesterase 6 inhibition by its gamma-subunit.

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1
Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.

Abstract

The interaction of phosphodiesterase 6 (PDE6) with its inhibitory Pgamma-subunits (Pgamma) is unparalleled among PDE families and is central to vertebrate phototransduction. The C-terminus of Pgamma occludes the active site of PDE6, thereby preventing hydrolysis of cGMP. In this study, we examine the determinants of this critical interaction using structure-based loss-of-function mutagenesis of a chimeric PDE5/PDE6 catalytic domain and gain-of-function mutagenesis of the PDE5 catalytic domain. This analysis revealed the key role of PDE6-specific residues within the catalytic domain M-loop-alpha-helix 15 region and suggested an important contribution of the H-loop-M-loop interface to the PDE6 inhibition by the Pgamma C-terminus. Identification of the determinants for the PDE6-Pgamma interaction offers insights into the evolution of the visual effector enzyme.

PMID:
20397626
PMCID:
PMC2864356
DOI:
10.1021/bi100354a
[Indexed for MEDLINE]
Free PMC Article
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