Journal article
Structural basis of phosphodiesterase-5 conformational organization revealed by a PDE6/PDE5 Chimera
The Journal of biological chemistry, Vol.302(6), 111467
06/2026
DOI: 10.1016/j.jbc.2026.111467
PMCID: PMC13199883
PMID: 42001945
Abstract
Phosphodiesterase 5 (PDE5) plays critical role in the nitric oxide-cGMP signaling pathway. Consequently, PDE5 catalytic site inhibitors are widely used in the treatment of erectile dysfunction and pulmonary arterial hypertension. Despite a wealth of structural data on the individual PDE5 catalytic domain with bound drug molecules, understanding of the structural organization of the full-length enzyme and its allosteric activation by noncatalytic cGMP-binding is lacking. To begin to understand the structural organization of PDE5, we solved a cryo-EM structure of a chimeric PDE enzyme (PDE6C/5) comprised of the regulatory domains of cone PDE6C and the PDE5 catalytic domain. The PDE6C/5 structure revealed the protein in the open state conformation similar to that of PDE6, suggesting a comparable conformation for the cGMP-bound PDE5 molecule. The H- and M-loops outlying the catalytic pocket, which are conformationally variable in the structures of isolated PDE5 catalytic domain, are immobilized in the PDE6/5 chimera via the interaction of the H-loop with a linker helix LH2. Decreased dynamics of these loops may underlie the higher catalytic activities of the full-length PDE5 and PDE6C/5 compared to that of the isolated PDE5 catalytic domain. Furthermore, the PDE6C/5 structure defines the folding requirement of the PDE6 catalytic domain for chaperone-dependent maturation that is important for vision.
Details
- Title: Subtitle
- Structural basis of phosphodiesterase-5 conformational organization revealed by a PDE6/PDE5 Chimera
- Creators
- Dhiraj Srivastava - Department of Molecular Physiology and BiophysicsSneha Singh - Department of Molecular Physiology and BiophysicsChris Yu - University of IowaKimberly Boyd - Department of Molecular Physiology and BiophysicsNikolai O Artemyev - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.302(6), 111467
- DOI
- 10.1016/j.jbc.2026.111467
- PMID
- 42001945
- PMCID
- PMC13199883
- NLM abbreviation
- J Biol Chem
- ISSN
- 1083-351X
- eISSN
- 1083-351X
- Publisher
- Elsevier; AMSTERDAM
- Grant note
- National Institutes of Health: RO1 EY-10843 Pediatric Ophthalmology Career Starter Research Grant from the Knights Templar Eye Foundation NIH: U24GM129547 Office of Biological and Environmental Research
This work was supported by the National Institutes of Health grant RO1 EY-10843 to N. O. A. S. S. was supported by Pediatric Ophthalmology Career Starter Research Grant from the Knights Templar Eye Foundation. A portion of this research was supported by NIH grant U24GM129547 and performed at the PNCC at OHSU and accessed through EMSL (grid.436923.9) , a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research.
- Language
- English
- Electronic publication date
- 04/17/2026
- Date published
- 06/2026
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
- Record Identifier
- 9985155644702771
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