Structural basis of phosphodiesterase 6 inhibition by the C-terminal region of the γ-subunit

Brandy Barren; Lokesh Gakhar; Hakim Muradov; Kimberly K Boyd; S Ramaswamy; Nikolai O Artemyev

doi:10.1038/emboj.2009.284

Back

Structural basis of phosphodiesterase 6 inhibition by the C-terminal region of the γ-subunit

Journal article

Open access

Peer reviewed

Structural basis of phosphodiesterase 6 inhibition by the C-terminal region of the γ-subunit

Brandy Barren, Lokesh Gakhar, Hakim Muradov, Kimberly K Boyd, S Ramaswamy and Nikolai O Artemyev

The EMBO journal, Vol.28(22), pp.3613-3622

11/18/2009

DOI: 10.1038/emboj.2009.284

PMCID: PMC2782096

PMID: 19798052

Files and links (1)

url

https://doi.org/10.1038/emboj.2009.284View

Published (Version of record) Open Access

Abstract

The inhibitory interaction of phosphodiesterase-6 (PDE6) with its γ-subunit (Pγ) is pivotal in vertebrate phototransduction. Here, crystal structures of a chimaeric PDE5/PDE6 catalytic domain (PDE5/6cd) complexed with sildenafil or 3-isobutyl-1-methylxanthine and the Pγ-inhibitory peptide Pγ 70−87 have been determined at 2.9 and 3.0 Å, respectively. These structures show the determinants and the mechanism of the PDE6 inhibition by Pγ and suggest the conformational change of Pγ on transducin activation. Two variable H- and M-loops of PDE5/6cd form a distinct interface that contributes to the Pγ-binding site. This allows the Pγ C-terminus to fit into the opening of the catalytic pocket, blocking cGMP access to the active site. Our analysis suggests that disruption of the H–M loop interface and Pγ-binding site is a molecular cause of retinal degeneration in atrd3 mice. Comparison of the two PDE5/6cd structures shows an overlap between the sildenafil and Pγ 70−87 -binding sites, thereby providing critical insights into the side effects of PDE5 inhibitors on vision.

X-ray crystallography

transducin

phototransduction

phosphodiesterase 6

Details

Title: Subtitle: Structural basis of phosphodiesterase 6 inhibition by the C-terminal region of the γ-subunit
Creators: Brandy Barren - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA
Lokesh Gakhar - Department of Biochemistry, University of Iowa, Iowa City, IA, USA
Hakim Muradov - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA
Kimberly K Boyd - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA
S Ramaswamy - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA
Nikolai O Artemyev - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: The EMBO journal, Vol.28(22), pp.3613-3622
DOI: 10.1038/emboj.2009.284
PMID: 19798052
PMCID: PMC2782096
NLM abbreviation: EMBO J
ISSN: 0261-4189
eISSN: 1460-2075
Publisher: Nature Publishing Group
Alternative title: Inhibition of phosphodiesterase 6 by the γ-subunit
Language: English
Date published: 11/18/2009
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology; Medicine Administration; Ophthalmology and Visual Sciences
Record Identifier: 9984025368202771

Metrics

15 Record Views

52 Times Cited - Web of Science