A novel binding pocket of cyclin‐dependent kinase 2

Chen, Hao; Duyne, Rachel Van; Zhang, Naigong; Kashanchi, Fatah; Zeng, Chen

doi:10.1002/prot.22136

Cited by 19 publications

(28 citation statements)

References 24 publications

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“…The network representation (C) and surface model (D) of p7 pocket indicate that Tyr180 (position 4) and Pro271 (position 12) may be the crucial residues for p7 (TL) pocket from CLK1 kinase in the CMGC group. This observation agrees with previous experiments 24,40. 2008 | RSC Adv., 2020,10,[2004][2005][2006][2007][2008][2009][2010][2011][2012][2013][2014][2015] This journal is © The Royal Society of Chemistry 2020RSC Advances PaperOpen Access Article.…”

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confidence: 94%

Novel method to identify group-specific non-catalytic pockets of human kinome for drug design

et al. 2020

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supporting

confidence: 94%

Novel method to identify group-specific non-catalytic pockets of human kinome for drug design

et al. 2020

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“…In particular, two double mutants TAALS and LAALS of the wild type Tat peptide TKALG (K41A and G44S) are potent kinase inhibitors that disrupt the Cyclin/CDK complex formation. Specifically, in functional kinase inhibition assays using the C-terminal domain (CTD) of RNA polymerase II as a substrate, we observed an IC 50 of 26.1 μM for TAALS and 4.26 μM for LAALS peptides 12 . Using a series of alanine mutagenesis on CDK2, we demonstrated that these peptides interact with CDK2 directly at a binding pocket near the interface of the Cyclin/CDK complex 6 , a result also obtained by computational docking programs whose docking conformation is displayed in Figure 1A, where two key residues of CDK2, Lys178 and Tyr180, required for the binding interaction are labeled 6 .…”

Section: Resultsmentioning

confidence: 93%

“…For CDK9, the conformation was obtained from PDB 3BLH. We followed the docking procedure exactly as previously described in details by Chen et al, 2008 including all specific parameters used in the simulated annealing 12 . Global dockings of LAALS onto CDK2 and CDK9were performed to locate the binding pockets as shown in Figure 1(A)-(B).…”

Section: Methodsmentioning

confidence: 99%

Effect of Mimetic CDK9 Inhibitors on HIV-1-Activated Transcription

Duyne

Guendel

Jaworski

et al. 2013

Journal of Molecular Biology

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Potent antiretroviral therapy (ART) has transformed HIV-1 infection into a chronic manageable disease; however drug resistance remains a common problem that limits the effectiveness and clinical benefits of this type of treatment. The discovery of viral reservoirs in the body, in which HIV-1 may persist, has helped to explain why therapeutic eradication of HIV-1 has proved so difficult. In the current study we utilized a combination of structure based analysis of Cyclin/CDK complexes with our previously published Tat peptide derivatives. We modeled the Tat peptide inhibitors with CDKs and found a particular pocket which showed the most stable binding site (Cavity 1) using in silico analysis. Furthermore, we were able to find peptide mimetics that bound to similar regions using in silico searches of a chemical library, followed by cell based biological assays. Using these methods we obtained the first generation mimetic drugs and tested these compounds on HIV-1 LTR activated transcription. Using biological assays followed by similar in silico analysis to find a 2nd generation drugs resembling the original mimetic, we found the new targets of Cavity 1 and Cavity 2 regions on CDK9. We examined the 2nd generation mimetic against various viral isolates, and observed a generalized suppression of most HIV-1 isolates. Finally, the drug inhibited viral replication in humanized mouse models of Rag2-/-γc-/- with no toxicity to the animals at tested concentrations. Our results suggest that it may be possible to model peptide inhibitors into available crystal structures and further find drug mimetics using in silico analysis.

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“…Molecular dynamics simulations of interactions between putative BH3 sequences and anti-apoptotic BCL2 family members were carried out essentially as we have described previously [21] except that GROMACS (Groningen Machine for Chemical Simulations) was used as the modeling software (www.gromacs.org) [22]. The starting coordinates for the simulations of the binding of the 25-mer AVEN and dAven peptides to BCL-xL were based on the BAD/BCL-xL complex (PDB code: 1G5J) [4].…”

Section: Materials and Methodologymentioning

confidence: 99%

An Integrated Bioinformatics and Computational Biology Approach Identifies New BH3-Only Protein Candidates

Hawley

Chen²,

Riz³

et al. 2012

TOBIOJ

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In this study, we utilized an integrated bioinformatics and computational biology approach in search of new BH3-only proteins belonging to the BCL2 family of apoptotic regulators. The BH3 (BCL2 homology 3) domain mediates specific binding interactions among various BCL2 family members. It is composed of an amphipathic α-helical region of approximately 13 residues that has only a few amino acids that are highly conserved across all members. Using a generalized motif, we performed a genome-wide search for novel BH3-containing proteins in the NCBI Consensus Coding Sequence (CCDS) database. In addition to known pro-apoptotic BH3-only proteins, 197 proteins were recovered that satisfied the search criteria. These were categorized according to α-helical content and predictive binding to BCL-xL (encoded by BCL2L1) and MCL-1, two representative anti-apoptotic BCL2 family members, using position-specific scoring matrix models. Notably, the list is enriched for proteins associated with autophagy as well as a broad spectrum of cellular stress responses such as endoplasmic reticulum stress, oxidative stress, antiviral defense, and the DNA damage response. Several potential novel BH3-containing proteins are highlighted. In particular, the analysis strongly suggests that the apoptosis inhibitor and DNA damage response regulator, AVEN, which was originally isolated as a BCL-xL-interacting protein, is a functional BH3-only protein representing a distinct subclass of BCL2 family members.

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A novel binding pocket of cyclin‐dependent kinase 2

Cited by 19 publications

References 24 publications

Novel method to identify group-specific non-catalytic pockets of human kinome for drug design

Novel method to identify group-specific non-catalytic pockets of human kinome for drug design

Effect of Mimetic CDK9 Inhibitors on HIV-1-Activated Transcription

An Integrated Bioinformatics and Computational Biology Approach Identifies New BH3-Only Protein Candidates

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