Crystal structures of human RIP2 kinase catalytic domain complexed with ATP-competitive inhibitors: Foundations for understanding inhibitor selectivity

2015 ◽  
Vol 23 (21) ◽  
pp. 7000-7006 ◽  
Author(s):  
Adam K. Charnley ◽  
Máire A. Convery ◽  
Ami Lakdawala Shah ◽  
Emma Jones ◽  
Philip Hardwicke ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Catalytic Domain ◽  
Kinase Catalytic Domain ◽  
Competitive Inhibitors ◽  
Inhibitor Selectivity

scholarly journals A Unique GTP-Dependent Sporulation Sensor Histidine Kinase in Bacillus anthracis

2008 ◽  
Vol 191 (3) ◽  
pp. 687-692 ◽  
Author(s):  
Francesca Scaramozzino ◽  
Andrea White ◽  
Marta Perego ◽  
James A. Hoch
Keyword(s):  
Bacillus Anthracis ◽  
Histidine Kinase ◽  
Catalytic Domain ◽  
Coiled Coil ◽  
Reverse Reaction ◽  
Forward Reaction ◽  
Critical Signal ◽  
Sensor Histidine Kinase ◽  
Virulence Plasmids ◽  
Kinase Catalytic Domain

ABSTRACT The Bacillus anthracis BA2291 gene codes for a sensor histidine kinase involved in the induction of sporulation. Genes for orthologs of the sensor domain of the BA2291 kinase exist in virulence plasmids in this organism, and these proteins, when expressed, inhibit sporulation by converting BA2291 to an apparent phosphatase of the sporulation phosphorelay. Evidence suggests that the sensor domains inhibit BA2291 by titrating its activating signal ligand. Studies with purified BA2291 revealed that this kinase is uniquely specific for GTP in the forward reaction and GDP in the reverse reaction. The G1 motif of BA2291 is highly modified from ATP-specific histidine kinases, and modeling this motif in the structure of the kinase catalytic domain suggested how guanine binds to the region. A mutation in the putative coiled-coil linker between the sensor domain and the catalytic domains was found to decrease the rate of the forward autophosphorylation reaction and not affect the reverse reaction from phosphorylated Spo0F. The results suggest that the activating ligand for BA2291 is a critical signal for sporulation and in a limited concentration in the cell. Decreasing the response to it either by slowing the forward reaction through mutation or by titration of the ligand by expressing the plasmid-encoded sensor domains switches BA2291 from an inducer to an inhibitor of the phosphorelay and sporulation.

scholarly journals Insights into the regulation of eukaryotic elongation factor 2 kinase and the interplay between its domains

2012 ◽  
Vol 442 (1) ◽  
pp. 105-118 ◽  
Author(s):  
Craig R. Pigott ◽  
Halina Mikolajek ◽  
Claire E. Moore ◽  
Stephen J. Finn ◽  
Curtis W. Phippen ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Catalytic Domain ◽  
Functional Organization ◽  
Elongation Factor ◽  
Kinase Domain ◽  
Conserved Residues ◽  
Elongation Factor 2 ◽  
Eukaryotic Elongation Factor 2 ◽  
Kinase Catalytic Domain ◽  
Eukaryotic Elongation Factor

eEF2K (eukaryotic elongation factor 2 kinase) is a Ca2+/CaM (calmodulin)-dependent protein kinase which regulates the translation elongation machinery. eEF2K belongs to the small group of so-called ‘α-kinases’ which are distinct from the main eukaryotic protein kinase superfamily. In addition to the α-kinase catalytic domain, other domains have been identified in eEF2K: a CaM-binding region, N-terminal to the kinase domain; a C-terminal region containing several predicted α-helices (resembling SEL1 domains); and a probably rather unstructured ‘linker’ region connecting them. In the present paper, we demonstrate: (i) that several highly conserved residues, implicated in binding ATP or metal ions, are critical for eEF2K activity; (ii) that Ca2+/CaM enhance the ability of eEF2K to bind to ATP, providing the first insight into the allosteric control of eEF2K; (iii) that the CaM-binding/α-kinase domain of eEF2K itself possesses autokinase activity, but is unable to phosphorylate substrates in trans; (iv) that phosphorylation of these substrates requires the SEL1-like domains of eEF2K; and (v) that highly conserved residues in the C-terminal tip of eEF2K are essential for the phosphorylation of eEF2, but not a peptide substrate. On the basis of these findings, we propose a model for the functional organization and control of eEF2K.

Crystal Structures of Anaplastic Lymphoma Kinase in Complex with ATP Competitive Inhibitors

Biochemistry ◽  
2010 ◽  
Vol 49 (32) ◽  
pp. 6813-6825 ◽  
Author(s):  
Roberto T. Bossi ◽  
M. Beatrice Saccardo ◽  
Elena Ardini ◽  
Maria Menichincheri ◽  
Luisa Rusconi ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Anaplastic Lymphoma Kinase ◽  
Anaplastic Lymphoma ◽  
Competitive Inhibitors

Expression, Purification and Crystallisation of Phosphorylase Kinase Catalytic Domain

1995 ◽  
Vol 246 (3) ◽  
pp. 374-381 ◽  
Author(s):  
D.J. Owen ◽  
A.C. Papageorgiou ◽  
E.F. Garman ◽  
M.E.M. Noble ◽  
L.N. Johnson
Keyword(s):  
Catalytic Domain ◽  
Phosphorylase Kinase ◽  
Kinase Catalytic Domain

scholarly journals Homodimerization of the Death-Associated Protein Kinase Catalytic Domain: Development of a New Small Molecule Fluorescent Reporter

PLoS ONE ◽  
2010 ◽  
Vol 5 (11) ◽  
pp. e14120 ◽  
Author(s):  
Michael Zimmermann ◽  
Cédric Atmanene ◽  
Qingyan Xu ◽  
Laetitia Fouillen ◽  
Alain Van Dorsselaer ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Small Molecule ◽  
Catalytic Domain ◽  
Fluorescent Reporter ◽  
Kinase Catalytic Domain ◽  
Death Associated Protein Kinase

scholarly journals Mapping of the Novel Protein Kinase Catalytic Domain ofDictyosteliumMyosin II Heavy Chain Kinase A

1997 ◽  
Vol 272 (11) ◽  
pp. 6846-6849 ◽  
Author(s):  
Graham P. Côté ◽  
Xia Luo ◽  
Michael B. Murphy ◽  
Thomas T. Egelhoff
Keyword(s):  
Protein Kinase ◽  
Heavy Chain ◽  
Catalytic Domain ◽  
The Novel ◽  
Kinase Catalytic Domain ◽  
Kinase A ◽  
Novel Protein

scholarly journals Fine mapping of Brassica napus blackleg resistance gene Rlm1 through bulked segregant RNA sequencing

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Fuyou Fu ◽  
Xunjia Liu ◽  
Rui Wang ◽  
Chun Zhai ◽  
Gary Peng ◽  
...  
Keyword(s):  
Brassica Napus ◽  
Resistance Gene ◽  
Rna Sequencing ◽  
Catalytic Domain ◽  
Leptosphaeria Maculans ◽  
Snp Markers ◽  
Specific Pcr ◽  
Dual Specificity ◽  
Kinase Catalytic Domain ◽  
Allele Specific

Abstract The fungal pathogen Leptosphaeria maculans causes blackleg disease on canola and rapeseed (Brassica napus) in many parts of the world. A B. napus cultivar, ‘Quinta’, has been widely used for the classification of L. maculans into pathogenicity groups. In this study, we confirmed the presence of Rlm1 in a DH line (DH24288) derived from B. napus cultivar ‘Quinta’. Rlm1 was located on chromosome A07, between 13.07 to 22.11 Mb, using a BC1 population made from crosses of F1 plants of DH16516 (a susceptible line) x DH24288 with bulked segregant RNA Sequencing (BSR-Seq). Rlm1 was further fine mapped in a 100 kb region from 19.92 to 20.03 Mb in the BC1 population consisting of 1247 plants and a F2 population consisting of 3000 plants using SNP markers identified from BSR-Seq through Kompetitive Allele-Specific PCR (KASP). A potential resistance gene, BnA07G27460D, was identified in this Rlm1 region. BnA07G27460D encodes a serine/threonine dual specificity protein kinase, catalytic domain and is homologous to STN7 in predicted genes of B. rapa and B. oleracea, and A. thaliana. Robust SNP markers associated with Rlm1 were developed, which can assist in introgression of Rlm1 and confirm the presence of Rlm1 gene in canola breeding programs.

scholarly journals Genetic Evidence for Pak1 Autoinhibition and Its Release by Cdc42

1999 ◽  
Vol 19 (1) ◽  
pp. 602-611 ◽  
Author(s):  
Hua Tu ◽  
Mike Wigler
Keyword(s):  
Protein Kinase ◽  
Hybrid System ◽  
Sexual Differentiation ◽  
Catalytic Domain ◽  
Intramolecular Interaction ◽  
Intramolecular Interactions ◽  
Regulatory Domain ◽  
Kinase Catalytic Domain ◽  
Two Hybrid ◽  
Open Configuration

ABSTRACT Pak1 protein kinase of Schizosaccharomyces pombe, a member of the p21-GTPase-activated protein kinase (PAK) family, participates in signaling pathways including sexual differentiation and morphogenesis. The regulatory domain of PAK proteins is thought to inhibit the kinase catalytic domain, as truncation of this region renders kinases more active. Here we report the detection in the two-hybrid system of the interaction between Pak1 regulatory domain and the kinase catalytic domain. Pak1 catalytic domain binds to the same highly conserved region on the regulatory domain that binds Cdc42, a GTPase protein capable of activating Pak1. Two-hybrid, mutant, and genetic analyses indicated that this intramolecular interaction rendered the kinase in a closed and inactive configuration. We show that Cdc42 can induce an open configuration of Pak1. We propose that Cdc42 interaction disrupts the intramolecular interactions of Pak1, thereby releasing the kinase from autoinhibition.

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