GK4, a G-protein-coupled receptor with a phosphatidylinositol phosphate kinase domain inPhytophthora infestans, is involved in sporangia development and virulence

2013 ◽  
Vol 88 (2) ◽  
pp. 352-370 ◽  
Author(s):  
Chenlei Hua ◽  
Harold J. G. Meijer ◽  
Jeroen de Keijzer ◽  
Wei Zhao ◽  
Yuanchao Wang ◽  
...  
Keyword(s):  
G Protein ◽  
Kinase Domain ◽  
G Protein Coupled Receptor ◽  
Phosphatidylinositol Phosphate ◽  
G Protein Coupled ◽  
Phosphatidylinositol Phosphate Kinase

scholarly journals Crystal Structure of G Protein-coupled Receptor Kinase 5 in Complex with a Rationally Designed Inhibitor

2015 ◽  
Vol 290 (34) ◽  
pp. 20649-20659 ◽  
Author(s):  
Kristoff T. Homan ◽  
Helen V. Waldschmidt ◽  
Alisa Glukhova ◽  
Alessandro Cannavo ◽  
Jianliang Song ◽  
...  
Keyword(s):  
Crystal Structure ◽  
G Protein ◽  
Active Site ◽  
Parent Compound ◽  
Kinase Domain ◽  
Kinetic Properties ◽  
G Protein Coupled Receptor ◽  
Structure Based Drug Design ◽  
Terminal Structure ◽  
G Protein Coupled

G protein-coupled receptor kinases (GRKs) regulate cell signaling by initiating the desensitization of active G protein-coupled receptors. The two most widely expressed GRKs (GRK2 and GRK5) play a role in cardiovascular disease and thus represent important targets for the development of novel therapeutic drugs. In the course of a GRK2 structure-based drug design campaign, one inhibitor (CCG215022) exhibited nanomolar IC50 values against both GRK2 and GRK5 and good selectivity against other closely related kinases such as GRK1 and PKA. Treatment of murine cardiomyocytes with CCG215022 resulted in significantly increased contractility at 20-fold lower concentrations than paroxetine, an inhibitor with more modest selectivity for GRK2. A 2.4 Å crystal structure of the GRK5·CCG215022 complex was determined and revealed that the inhibitor binds in the active site similarly to its parent compound GSK180736A. As designed, its 2-pyridylmethyl amide side chain occupies the hydrophobic subsite of the active site where it forms three additional hydrogen bonds, including one with the catalytic lysine. The overall conformation of the GRK5 kinase domain is similar to that of a previously determined structure of GRK6 in what is proposed to be its active state, but the C-terminal region of the enzyme adopts a distinct conformation. The kinetic properties of site-directed mutants in this region are consistent with the hypothesis that this novel C-terminal structure is representative of the membrane-bound conformation of the enzyme.

scholarly journals A G Protein-Coupled Receptor with a Lipid Kinase Domain Is Involved in Cell-Density Sensing

2007 ◽  
Vol 17 (10) ◽  
pp. 892-897 ◽  
Author(s):  
Deenadayalan Bakthavatsalam ◽  
Derrick Brazill ◽  
Richard H. Gomer ◽  
Ludwig Eichinger ◽  
Francisco Rivero ◽  
...  
Keyword(s):  
G Protein ◽  
Cell Density ◽  
Kinase Domain ◽  
G Protein Coupled Receptor ◽  
Lipid Kinase ◽  
G Protein Coupled

scholarly journals Activation of G Protein-Coupled Receptor Kinase 1 Involves Interactions between Its N-Terminal Region and Its Kinase Domain

Biochemistry ◽  
2011 ◽  
Vol 50 (11) ◽  
pp. 1940-1949 ◽  
Author(s):  
Chih-chin Huang ◽  
Tivadar Orban ◽  
Beata Jastrzebska ◽  
Krzysztof Palczewski ◽  
John J. G. Tesmer
Keyword(s):  
G Protein ◽  
Kinase Domain ◽  
Terminal Region ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals Atomic Structure of GRK5 Reveals Distinct Structural Features Novel for G Protein-coupled Receptor Kinases

2015 ◽  
Vol 290 (34) ◽  
pp. 20629-20647 ◽  
Author(s):  
Konstantin E. Komolov ◽  
Anshul Bhardwaj ◽  
Jeffrey L. Benovic
Keyword(s):  
G Protein ◽  
High Mobility ◽  
Binding Pocket ◽  
Structural Features ◽  
Kinase Domain ◽  
G Protein Coupled Receptor ◽  
The Family ◽  
Receptor Kinases ◽  
Novel Interactions ◽  
G Protein Coupled

G protein-coupled receptor kinases (GRKs) are members of the protein kinase A, G, and C families (AGC) and play a central role in mediating G protein-coupled receptor phosphorylation and desensitization. One member of the family, GRK5, has been implicated in several human pathologies, including heart failure, hypertension, cancer, diabetes, and Alzheimer disease. To gain mechanistic insight into GRK5 function, we determined a crystal structure of full-length human GRK5 at 1.8 Å resolution. GRK5 in complex with the ATP analog 5′-adenylyl β,γ-imidodiphosphate or the nucleoside sangivamycin crystallized as a monomer. The C-terminal tail (C-tail) of AGC kinase domains is a highly conserved feature that is divided into three segments as follows: the C-lobe tether, the active-site tether (AST), and the N-lobe tether (NLT). This domain is fully resolved in GRK5 and reveals novel interactions with the nucleotide and N-lobe. Similar to other AGC kinases, the GRK5 AST is an integral part of the nucleotide-binding pocket, a feature not observed in other GRKs. The AST also mediates contact between the kinase N- and C-lobes facilitating closure of the kinase domain. The GRK5 NLT is largely displaced from its previously observed position in other GRKs. Moreover, although the autophosphorylation sites in the NLT are >20 Å away from the catalytic cleft, they are capable of rapid cis-autophosphorylation suggesting high mobility of this region. In summary, we provide a snapshot of GRK5 in a partially closed state, where structural elements of the kinase domain C-tail are aligned to form novel interactions to the nucleotide and N-lobe not previously observed in other GRKs.

Novel phosphatidylinositol phosphate kinases with a G-protein coupled receptor signature are shared by Dictyostelium and Phytophthora

2006 ◽  
Vol 14 (9) ◽  
pp. 378-382 ◽  
Author(s):  
Deenadayalan Bakthavatsalam ◽  
Harold J.G. Meijer ◽  
Angelika A. Noegel ◽  
Francine Govers
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptor ◽  
Phosphatidylinositol Phosphate ◽  
G Protein Coupled
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