4QX5

Neutron diffraction reveals hydrogen bonds critical for cGMP-selective activation: Insights for PKG agonist design

Summary for 4QX5

• Entry DOI: 10.2210/pdb4qx5/pdb
• Descriptor: cGMP-dependent protein kinase 1, ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE, IODIDE ION, ... (4 entities in total)
• Functional Keywords: phosphate binding cassette/cyclic gmp binding domain/pkg, serine/threonine kinase, cyclic gmp, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : Q13976
• Total number of polymer chains: 1
• Total formula weight: 19559.29

Authors

Huang, G.Y.,Gerlits, O.O.,Blakeley, M.P.,Sankaran, B.,Kovalevsky, A.Y.,Kim, C. (deposition date: 2014-07-18, release date: 2014-11-12, Last modification date: 2024-02-28)

Primary citation

Huang, G.Y.,Gerlits, O.O.,Blakeley, M.P.,Sankaran, B.,Kovalevsky, A.Y.,Kim, C.
Neutron Diffraction Reveals Hydrogen Bonds Critical for cGMP-Selective Activation: Insights for cGMP-Dependent Protein Kinase Agonist Design.
Biochemistry, 53:6725-6727, 2014

PubMed Abstract: High selectivity of cyclic-nucleotide binding (CNB) domains for cAMP and cGMP are required for segregating signaling pathways; however, the mechanism of selectivity remains unclear. To investigate the mechanism of high selectivity in cGMP-dependent protein kinase (PKG), we determined a room-temperature joint X-ray/neutron (XN) structure of PKG Iβ CNB-B, a domain 200-fold selective for cGMP over cAMP, bound to cGMP (2.2 Å), and a low-temperature X-ray structure of CNB-B with cAMP (1.3 Å). The XN structure directly describes the hydrogen bonding interactions that modulate high selectivity for cGMP, while the structure with cAMP reveals that all these contacts are disrupted, explaining its low affinity for cAMP.

PubMed: 25271401
DOI: 10.1021/bi501012v

Experimental method

X-RAY DIFFRACTION (1.318 Å)