Background: cGMP-dependent protein kinases utilize their leucine zipper (LZ) domains to bind interacting proteins in an isotype-specific manner. Results: Structural and biophysical analysis reveals residues for the PKG II-Rab11b interaction. Conclusion: PKG II utilizes an electroneutral surface on the LZ domain to bind Rab11b. Significance: This is the first structure of PKG bound to one of its interacting proteins.

cGMP-dependent protein kinase (PKG) Iα is a central regulator of smooth muscle tone and vasorelaxation. The N-terminal leucine zipper (LZ) domain dimerizes and targets PKG Iα by interacting with G-kinase-anchoring proteins. The PKG Iα LZ contains C42 that is known to form a disulfide bond upon oxidation and to activate PKG Iα. To understand the molecular details of the PKG Iα LZ and C42–C42′ disulfide bond, we determined crystal structures of the PKG Iα wild-type (WT) LZ and C42L LZ. Our data demonstrate that the C42–C42′ disulfide bond dramatically stabilizes PKG Iα and that the C42L mutant mimics the oxidized WT LZ structurally.

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