7LV3

Crystal structure of human protein kinase G (PKG) R-C complex in inhibited state

7LV3 の概要

• エントリーDOI: 10.2210/pdb7lv3/pdb
• 分子名称: Isoform Beta of cGMP-dependent protein kinase 1, MANGANESE (II) ION, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (5 entities in total)
• 機能のキーワード: protein kinase g, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 141141.43

構造登録者

Sharma, R.,Lying, Q.,Casteel, D.,Kim, C. (登録日: 2021-02-23, 公開日: 2022-08-24, 最終更新日: 2024-11-20)

主引用文献

Sharma, R.,Kim, J.J.,Qin, L.,Henning, P.,Akimoto, M.,VanSchouwen, B.,Kaur, G.,Sankaran, B.,MacKenzie, K.R.,Melacini, G.,Casteel, D.E.,Herberg, F.W.,Kim, C.W.
An auto-inhibited state of protein kinase G and implications for selective activation.
Elife, 11:-, 2022

PubMed Abstract: Cyclic GMP-dependent protein kinases (PKGs) are key mediators of the nitric oxide/cyclic guanosine monophosphate (cGMP) signaling pathway that regulates biological functions as diverse as smooth muscle contraction, cardiac function, and axon guidance. Understanding how cGMP differentially triggers mammalian PKG isoforms could lead to new therapeutics that inhibit or activate PKGs, complementing drugs that target nitric oxide synthases and cyclic nucleotide phosphodiesterases in this signaling axis. Alternate splicing of PRKG1 transcripts confers distinct leucine zippers, linkers, and auto-inhibitory (AI) pseudo-substrate sequences to PKG Iα and Iβ that result in isoform-specific activation properties, but the mechanism of enzyme auto-inhibition and its alleviation by cGMP is not well understood. Here, we present a crystal structure of PKG Iβ in which the AI sequence and the cyclic nucleotide-binding (CNB) domains are bound to the catalytic domain, providing a snapshot of the auto-inhibited state. Specific contacts between the PKG Iβ AI sequence and the enzyme active site help explain isoform-specific activation constants and the effects of phosphorylation in the linker. We also present a crystal structure of a PKG I CNB domain with an activating mutation linked to Thoracic Aortic Aneurysms and Dissections. Similarity of this structure to wildtype cGMP-bound domains and differences with the auto-inhibited enzyme provide a mechanistic basis for constitutive activation. We show that PKG Iβ auto-inhibition is mediated by contacts within each monomer of the native full-length dimeric protein, and using the available structural and biochemical data we develop a model for the regulation and cooperative activation of PKGs.

PubMed: 35929723
DOI: 10.7554/eLife.79530

実験手法

X-RAY DIFFRACTION (2.41 Å)