Insights into the Structural Basis of N2 and O6 Substituted Guanine Derivatives as Cyclin-Dependent Kinase 2 (CDK2) Inhibitors: Prediction of the Binding Modes and Potency of the inhibitors by Docking and ONIOM Calculations

2009 ◽  
Vol 49 (4) ◽  
pp. 886-899 ◽  
Author(s):  
Jans H. Alzate-Morales ◽  
Julio Caballero ◽  
Ariela Vergara Jague ◽  
Fernando D. González Nilo
Keyword(s):  
Structural Basis ◽  
Binding Modes ◽  
Cyclin Dependent Kinase ◽  
Guanine Derivatives ◽  
Oniom Calculations

scholarly journals Structural basis of AdoMet-dependent aminocarboxypropyl transfer reaction catalyzed by tRNA-wybutosine synthesizing enzyme, TYW2

2009 ◽  
Vol 106 (37) ◽  
pp. 15616-15621 ◽  
Author(s):  
Masataka Umitsu ◽  
Hiroshi Nishimasu ◽  
Akiko Noma ◽  
Tsutomu Suzuki ◽  
Ryuichiro Ishitani ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Binding Pocket ◽  
Structural Basis ◽  
Binding Modes ◽  
Substrate Binding Pocket ◽  
Methyl Group ◽  
Group Transfer ◽  
Canonical Class ◽  
Functional Analyses

S-adenosylmethionine (AdoMet) is a methyl donor used by a wide variety of methyltransferases, and it is also used as the source of an α-amino-α-carboxypropyl (“acp”) group by several enzymes. tRNA-yW synthesizing enzyme-2 (TYW2) is involved in the biogenesis of a hypermodified nucleotide, wybutosine (yW), and it catalyzes the transfer of the “acp” group from AdoMet to the C7 position of the imG-14 base, a yW precursor. This modified nucleoside yW is exclusively located at position 37 of eukaryotic tRNAPhe, and it ensures the anticodon-codon pairing on the ribosomal decoding site. Although this “acp” group has a significant role in preventing decoding frame shifts, the mechanism of the “acp” group transfer by TYW2 remains unresolved. Here we report the crystal structures and functional analyses of two archaeal homologs of TYW2 from Pyrococcus horikoshii and Methanococcus jannaschii. The in vitro mass spectrometric and radioisotope-labeling analyses confirmed that these archaeal TYW2 homologues have the same activity as yeast TYW2. The crystal structures verified that the archaeal TYW2 contains a canonical class-I methyltransferase (MTase) fold. However, their AdoMet-bound structures revealed distinctive AdoMet-binding modes, in which the “acp” group, instead of the methyl group, of AdoMet is directed to the substrate binding pocket. Our findings, which were confirmed by extensive mutagenesis studies, explain why TYW2 transfers the “acp” group, and not the methyl group, from AdoMet to the nucleobase.

scholarly journals Structural basis for the binding of SNAREs to the multisubunit tethering complex Dsl1

2020 ◽  
Author(s):  
Sophie M. Travis ◽  
Kevin DAmico ◽  
I-Mei Yu ◽  
Safraz Hamid ◽  
Gabriel Ramirez-Arellano ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Relative Orientation ◽  
Snare Complex ◽  
Structural Basis ◽  
Binding Modes ◽  
Range Interaction ◽  
X Ray ◽  
X Ray Crystallography ◽  
Long Range Interaction ◽  
Target Membrane

AbstractMultisubunit tethering complexes (MTCs) are large (250 to >750 kDa), conserved macromolecular machines that are essential for SNARE-mediated membrane fusion in all eukaryotes. MTCs are thought to function as organizers of membrane trafficking, mediating the initial, long-range interaction between a vesicle and its target membrane and promoting the formation of membrane-bridging SNARE complexes. Previously, we reported the structure of the Dsl1 complex, the simplest known MTC, which is essential for COPI-mediated transport from the Golgi to the endoplasmic reticulum (ER). This structure suggested how the Dsl1 complex might function to tether a vesicle to its target membrane by binding at one end to the COPI coat and at the other end to ER SNAREs. Here, we use x-ray crystallography to investigate these Dsl1-SNARE interactions in greater detail. The Dsl1 complex comprises three subunits that together form a two-legged structure with a central hinge. Our results show that distal regions of each leg bind N-terminal Habc domains of the ER SNAREs Sec20 (a Qb-SNARE) and Use1 (a Qc-SNARE). The observed binding modes appear to anchor the Dsl1 complex to the ER target membrane while simultaneously ensuring that both SNAREs are in open conformations with their SNARE motifs available for assembly. The proximity of the two SNARE motifs, and therefore their ability to enter the same SNARE complex, depends on the relative orientation of the two Dsl1 legs.

scholarly journals Structural basis for DNA recognition and allosteric control of the retinoic acid receptors RAR–RXR

2020 ◽  
Vol 48 (17) ◽  
pp. 9969-9985
Author(s):  
Judit Osz ◽  
Alastair G McEwen ◽  
Maxime Bourguet ◽  
Frédéric Przybilla ◽  
Carole Peluso-Iltis ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Dna Binding ◽  
Structural Dynamics ◽  
Binding Domain ◽  
Retinoic Acid Receptors ◽  
Structural Basis ◽  
Dna Binding Domain ◽  
Binding Modes ◽  
Dna Complexes ◽  
X Ray

Abstract Retinoic acid receptors (RARs) as a functional heterodimer with retinoid X receptors (RXRs), bind a diverse series of RA-response elements (RAREs) in regulated genes. Among them, the non-canonical DR0 elements are bound by RXR–RAR with comparable affinities to DR5 elements but DR0 elements do not act transcriptionally as independent RAREs. In this work, we present structural insights for the recognition of DR5 and DR0 elements by RXR–RAR heterodimer using x-ray crystallography, small angle x-ray scattering, and hydrogen/deuterium exchange coupled to mass spectrometry. We solved the crystal structures of RXR–RAR DNA-binding domain in complex with the Rarb2 DR5 and RXR–RXR DNA-binding domain in complex with Hoxb13 DR0. While cooperative binding was observed on DR5, the two molecules bound non-cooperatively on DR0 on opposite sides of the DNA. In addition, our data unveil the structural organization and dynamics of the multi-domain RXR–RAR DNA complexes providing evidence for DNA-dependent allosteric communication between domains. Differential binding modes between DR0 and DR5 were observed leading to differences in conformation and structural dynamics of the multi-domain RXR–RAR DNA complexes. These results reveal that the topological organization of the RAR binding element confer regulatory information by modulating the overall topology and structural dynamics of the RXR–RAR heterodimers.

scholarly journals Structural Basis for Design of New Purine-Based Inhibitors Targeting the Hydrophobic Binding Pocket of Hsp90

2020 ◽  
Vol 21 (24) ◽  
pp. 9377
Author(s):  
Sang Chul Shin ◽  
Ashraf K. El-Damasy ◽  
Ju Hyeon Lee ◽  
Seon Hee Seo ◽  
Ji Hyun Kim ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Inhibitory Activity ◽  
Hct116 Cell ◽  
Heat Shock Protein 90 ◽  
Binding Pocket ◽  
Hsp90 Inhibitor ◽  
Structural Basis ◽  
Binding Modes ◽  
Hydrophobic Moiety ◽  
The Impact

Inhibition of the molecular chaperone heat shock protein 90 (Hsp90) represents a promising approach for cancer treatment. BIIB021 is a highly potent Hsp90 inhibitor with remarkable anticancer activity; however, its clinical application is limited by lack of potency and response. In this study, we aimed to investigate the impact of replacing the hydrophobic moiety of BIIB021, 4-methoxy-3,5-dimethylpyridine, with various five-membered ring structures on the binding to Hsp90. A focused array of N7/N9-substituted purines, featuring aromatic and non-aromatic rings, was designed, considering the size of hydrophobic pocket B in Hsp90 to obtain insights into their binding modes within the ATP binding site of Hsp90 in terms of π–π stacking interactions in pocket B as well as outer α-helix 4 configurations. The target molecules were synthesized and evaluated for their Hsp90α inhibitory activity in cell-free assays. Among the tested compounds, the isoxazole derivatives 6b and 6c, and the sole six-membered derivative 14 showed favorable Hsp90α inhibitory activity, with IC50 values of 1.76 µM, 0.203 µM, and 1.00 µM, respectively. Furthermore, compound 14 elicited promising anticancer activity against MCF-7, SK-BR-3, and HCT116 cell lines. The X-ray structures of compounds 4b, 6b, 6c, 8, and 14 bound to the N-terminal domain of Hsp90 were determined in order to understand the obtained results and to acquire additional structural insights, which might enable further optimization of BIIB021.

scholarly journals Structural basis of divergent cyclin‐dependent kinase activation by Spy1/ RINGO proteins

2017 ◽  
Vol 36 (15) ◽  
pp. 2251-2262 ◽  
Author(s):  
Denise A McGrath ◽  
Bre‐Anne Fifield ◽  
Aimee H Marceau ◽  
Sarvind Tripathi ◽  
Lisa A Porter ◽  
...  
Keyword(s):  
Structural Basis ◽  
Cyclin Dependent Kinase ◽  
Kinase Activation

Structural Basis of the Interaction of Cyclin-Dependent Kinase 2 with Roscovitine and Its Analogues Having Bioisosteric Central Heterocycles

ChemPhysChem ◽  
2017 ◽  
Vol 18 (7) ◽  
pp. 785-795 ◽  
Author(s):  
Michaela Nekardová ◽  
Ladislava Vymětalová ◽  
Prashant Khirsariya ◽  
Silvia Kováčová ◽  
Michaela Hylsová ◽  
...  
Keyword(s):  
Structural Basis ◽  
Cyclin Dependent Kinase
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