scholarly journals The role of conserved water molecules in the catalytic domain of protein kinases

2009 ◽  
Vol 76 (3) ◽  
pp. 527-535 ◽  
Author(s):  
James D. R. Knight ◽  
Donald Hamelberg ◽  
J. Andrew McCammon ◽  
Rashmi Kothary
Keyword(s):  
Protein Kinases ◽  
Catalytic Domain ◽  
Water Molecules ◽  
Conserved Water Molecules

scholarly journals Conserved Water Molecules Stabilize the Ω-Loop in Class A β-Lactamases

2008 ◽  
Vol 52 (3) ◽  
pp. 1072-1079 ◽  
Author(s):  
Fabian Bös ◽  
Jürgen Pleiss
Keyword(s):  
Phylogenetic Analysis ◽  
High Resolution ◽  
Evolutionary Relationship ◽  
Water Molecules ◽  
Protein Residues ◽  
Class A ◽  
Conserved Water Molecules ◽  
Dense Cluster ◽  
The Relationship

ABSTRACT A set of 49 high-resolution (≤2.2 Å) structures of the TEM, SHV, and CTX-M class A β-lactamase families was systematically analyzed to investigate the role of conserved water molecules in the stabilization of the Ω-loop. Overall, 13 water molecules were found to be conserved in at least 45 structures, including two water positions which were found to be conserved in all structures. Of the 13 conserved water molecules, 6 are located at the Ω-loop, forming a dense cluster with hydrogen bonds to residues at the Ω-loop as well as to the rest of the protein. This layer of conserved water molecules is packed between the Ω-loop and the rest of the protein and acts as structural glue, which could reduce the flexibility of the Ω-loop. A correlation between conserved water molecules and conserved protein residues could in general not be detected, with the exception of the conserved water molecules at the Ω-loop. Furthermore, the evolutionary relationship between the three families, derived from the number of conserved water molecules, is similar to the relationship derived from phylogenetic analysis.

CONSERVED WATER MOLECULES IN X-RAY STRUCTURES HIGHLIGHT THE ROLE OF WATER IN INTRAMOLECULAR AND INTERMOLECULAR INTERACTIONS

2008 ◽  
Vol 06 (04) ◽  
pp. 775-788 ◽  
Author(s):  
EVGENIY AKSIANOV ◽  
OLGA ZANEGINA ◽  
ALEXANDER GRISHIN ◽  
SERGEY SPIRIN ◽  
ANNA KARYAGINA ◽  
...  
Keyword(s):  
Intermolecular Interactions ◽  
Protein Interactions ◽  
Active Sites ◽  
Three Dimensional ◽  
Water Molecules ◽  
Macromolecular Complexes ◽  
X Ray ◽  
Conserved Water Molecules ◽  
Related Proteins

Water molecules immobilized on a protein or DNA surface are known to play an important role in intramolecular and intermolecular interactions. Comparative analysis of related three-dimensional (3D) structures allows to predict the locations of such water molecules on the protein surface. We have developed and implemented the algorithm WLAKE detecting "conserved" water molecules, i.e. those located in almost the same positions in a set of superimposed structures of related proteins or macromolecular complexes. The problem is reduced to finding maximal cliques in a certain graph. Despite exponential algorithm complexity, the program works appropriately fast for dozens of superimposed structures. WLAKE was used to predict functionally significant water molecules in enzyme active sites (transketolases) as well as in intermolecular (ETS–DNA complexes) and intramolecular (thiol–disulfide interchange protein) interactions. The program is available online at .

A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA

2020 ◽  
Vol 7 (2) ◽  
pp. 205-211
Author(s):  
Kaynat Fatima ◽  
Syed Tasleem Raza ◽  
Ale Eba ◽  
Sanchita Srivastava ◽  
Farzana Mahdi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

The function of protein kinases is to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.

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