Signatures of the ATP-binding pocket as a basis for structural classification of the serine/threonine protein kinases of gram-positive bacteria

2012 ◽  
Vol 80 (5) ◽  
pp. 1363-1376 ◽  
Author(s):  
Natalia V. Zakharevich ◽  
Dmitry I. Osolodkin ◽  
Irena I. Artamonova ◽  
Vladimir A. Palyulin ◽  
Nikolay S. Zefirov ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Binding Pocket ◽  
Atp Binding ◽  
Structural Classification ◽  
Gram Positive ◽  
Gram Positive Bacteria

Classification of Bacteriocins from Gram-Positive Bacteria

2011 ◽  
pp. 29-53 ◽  
Author(s):  
Mary C. Rea ◽  
R. Paul Ross ◽  
Paul D. Cotter ◽  
Colin Hill
Keyword(s):  
Gram Positive ◽  
Gram Positive Bacteria

scholarly journals Acquisition of Sensitivity of Stress-activated Protein Kinases to the p38 Inhibitor, SB 203580, by Alteration of One or More Amino Acids within the ATP Binding Pocket

1998 ◽  
Vol 273 (25) ◽  
pp. 15605-15610 ◽  
Author(s):  
Rebecca J. Gum ◽  
Megan M. McLaughlin ◽  
Sanjay Kumar ◽  
Zhulun Wang ◽  
Michael J. Bower ◽  
...  
Keyword(s):  
Amino Acids ◽  
Protein Kinases ◽  
Binding Pocket ◽  
Atp Binding ◽  
P38 Inhibitor ◽  
Sb 203580

scholarly journals Dimerization of human Rio2 kinase/ATPase locks its ATP-binding site in an apo state

2019 ◽  
Author(s):  
Frédérique Maurice ◽  
Natacha Pérébaskine ◽  
Sébastien Fribourg
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Ribosome Biogenesis ◽  
Binding Pocket ◽  
Dual Function ◽  
Atp Binding ◽  
Oligomeric State ◽  
Self Association ◽  
Rio2 Kinase ◽  
Apo State

ABSTRACTRio proteins form a conserved family of atypical protein kinases. Rio2 is a serine/threonine protein kinase/ATPase involved in pre-40S ribosomal maturation. Current crystal structures of archaeal and fungi Rio2 proteins report a monomeric form of the protein. Here, we describe three atomic structures of the human Rio2 kinase showing that it forms a homodimer. Upon self-association, the ATP-binding pocket is hidden from the solvent and the protein is locked in an apo state corresponding to an inactive form of the kinase. The homodimerization is mediated by key residues previously shown to be responsible for ATP binding and catalysis. This unusual protein kinase dimer reveals an intricate mechanism of mutually exclusive substrate binding and oligomeric state formation. We propose that this oligomeric state could serve a dual function in maintaining the protein in an inactive state and being a novel type of nuclear import signal.Significance StatementRio kinases form a family of atypical protein kinases that are believed to be ATPases rather than kinases. The three members of the Rio family are involved in ribosome biogenesis. We show here that contrarily to what was reported so far, Rio2 is able homodimerize in a conformation that locks it in an apo state, preventing its (re)association to pre-mature ribosomes. This unconventional self-association is not seen in any other protein kinase. This mechanism is likely to be transient and could used to efficiently re-import the protein to the nucleus.

CW-PRED: A HMM-Based Method for the Classification of Cell Wall-Anchored Proteins of Gram-Positive Bacteria

2012 ◽  
pp. 285-290 ◽  
Author(s):  
Danai K. Fimereli ◽  
Konstantinos D. Tsirigos ◽  
Zoi I. Litou ◽  
Theodore D. Liakopoulos ◽  
Pantelis G. Bagos ◽  
...  
Keyword(s):  
Cell Wall ◽  
Gram Positive ◽  
Gram Positive Bacteria

scholarly journals Aromatic Rings as Molecular Determinants for the Molecular Recognition of Protein Kinase Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1776
Author(s):  
Yan Zhu ◽  
Saad Alqahtani ◽  
Xiche Hu
Keyword(s):  
Hydrogen Bonding ◽  
Molecular Recognition ◽  
Protein Kinases ◽  
Aromatic Ring ◽  
Kinase Inhibitors ◽  
Binding Pocket ◽  
Atp Binding ◽  
Aromatic Rings ◽  
Π Interactions ◽  
Molecular Determinants

Protein kinases are key enzymes in many signal transduction pathways, and play a crucial role in cellular proliferation, differentiation, and various cell regulatory processes. However, aberrant function of kinases has been associated with cancers and many other diseases. Consequently, competitive inhibition of the ATP binding site of protein kinases has emerged as an effective means of curing these diseases. Over the past three decades, thousands of protein kinase inhibitors (PKIs) with varying molecular frames have been developed. Large-scale data mining of the Protein Data Bank resulted in a database of 2139 non-redundant high-resolution X-ray crystal structures of PKIs bound to protein kinases. This provided us with a unique opportunity to study molecular determinants for the molecular recognition of PKIs. A chemoinformatic analysis of 2139 PKIs resulted in findings that PKIs are “flat” molecules with high aromatic ring counts and low fractions of sp3 carbon. All but one PKI possessed one or more aromatic rings. More importantly, it was found that the average weighted hydrogen bond count is inversely proportional to the number of aromatic rings. Based on this linear relationship, we put forward the exchange rule of hydrogen bonding interactions and non-bonded π-interactions. Specifically, a loss of binding affinity caused by a decrease in hydrogen bonding interactions is compensated by a gain in binding affinity acquired by an increase in aromatic ring-originated non-bonded interactions (i.e., π–π stacking interactions, CH–π interactions, cation–π interactions, etc.), and vice versa. The very existence of this inverse relationship strongly suggests that both hydrogen bonding and aromatic ring-originated non-bonded interactions are responsible for the molecular recognition of PKIs. As an illustration, two representative PKI–kinase complexes were employed to examine the relative importance of different modes of non-bonded interactions for the molecular recognition of PKIs. For this purpose, two FDA-approved PKI drugs, ibrutinib and lenvatinib, were chosen. The binding pockets of both PKIs were thoroughly examined to identify all non-bonded intermolecular interactions. Subsequently, the strengths of interaction energies between ibrutinib and its interacting residues in tyrosine kinase BTK were quantified by means of the double hybrid DFT method B2PLYP. The resulting energetics for the binding of ibrutinib in tyrosine kinase BTK showed that CH–π interactions and π–π stacking interactions between aromatic rings of the drug and hydrophobic residues in its binding pocket dominate the binding interactions. Thus, this work establishes that, in addition to hydrogen bonding, aromatic rings function as important molecular determinants for the molecular recognition of PKIs. In conclusion, our findings support the following pharmacophore model for ATP-competitive kinase inhibitors: a small molecule features a scaffold of one or more aromatic rings which is linked with one or more hydrophilic functional groups. The former has the structural role of acting as a scaffold and the functional role of participating in aromatic ring-originated non-bonded interactions with multiple hydrophobic regions in the ATP binding pocket of kinases. The latter ensure water solubility and form hydrogen bonds with the hinge region and other hydrophilic residues of the ATP binding pocket.

Protein Subcellular Localization Feature of Essential/Nonessential Genes in 28 Prokaryotes

2014 ◽  
Vol 644-650 ◽  
pp. 5197-5201
Author(s):  
Xiao Liu ◽  
Xiao Li Geng ◽  
Hong Ling Tang
Keyword(s):  
Subcellular Localization ◽  
Protein Sequences ◽  
Essential Genes ◽  
Protein Subcellular Localization ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Nonessential Gene ◽  
Nonessential Genes

This study aimed to pursue the correlation between essential/nonessential gene and protein subcellular localization. The protein sequences of the essential/nonessential genes of 28 prokaryotes in Database of Essential Genes were analyzed by PSORTb3.0. Results show that proteins of essential genes locate in cytoplasm with relatively high percentage, i.e., in the range of 40% to 55%. Percentages of the proteins of essential genes locate in cytoplasma membrane are lower than that of nonessential genes, which mostly are about 15%. However, the values of proteins of nonessential genes are mostly about 20%, and that of Gram-positive bacteria are close to 30%. The distributions of protein subcellular localization of the essential/nonessential genes are different evidently. This could be used for classification of essential and nonessential genes.

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