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Selective inhibition of BET bromodomains
A cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains is reported, establishing proof-of-concept for targeting protein–protein interactions of epigenetic ‘readers’, and providing a versatile chemical scaffold for the development of chemical probes more broadly throughout the b romodomain family. Expand
Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family
Bromodomains are protein interaction modules that specifically recognize ε-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks, and a structural mechanism for the simultaneous binding and recognition of diverse diacetyl-containing peptides by BRD4 is uncovered. Expand
Crystal structure of the tetrameric Mad1–Mad2 core complex: implications of a ‘safety belt’ binding mechanism for the spindle checkpoint
It is shown that unlocking the Mad2 C‐terminal tail is required for ligand release from Mad2, and that the ‘safety belt’ mechanism may prolong the lifetime of Mad2–ligand complexes. Expand
Critical Residues for Structure and Catalysis in Short-chain Dehydrogenases/Reductases*
This work has analyzed the role of several conserved residues regarding folding, stability, steady-state kinetics, and coenzyme binding using bacterial 3β/17β-hydroxysteroid dehydrogenase and selected mutants to form a tetrad of Asn-Ser-Tyr-Lys in the majority of characterized short-chain dehydrogenases/reductase enzymes. Expand
Linear Motif Atlas for Phosphorylation-Dependent Signaling
The resulting atlas of linear motifs revealed that oncogenic kinases tends to be less specific in the target sequences they phosphorylate than their non-oncogenic counterparts, that autophosphorylation sites tend to be more variable than other substrates of a given kinase, and that coupling interaction domains with kinase domains may allow phosphorylation site specificity to be low while still maintaining substrate specificity. Expand
Large-Scale Structural Analysis of the Classical Human Protein Tyrosine Phosphatome
22 human PTP crystal structures are presented that enable a comprehensive analysis of the classical PTP family and a “head-to-toe” dimerization model for RPTPγ/ζ is proposed that is distinct from the “inhibitory wedge” model and provides a molecular basis for inhibitory regulation. Expand
Structure of the CaMKIIδ/Calmodulin Complex Reveals the Molecular Mechanism of CaMKII Kinase Activation
Structural and biophysical studies reveal how CaMKII kinases, which are important for cellular learning and memory, are switched on by binding of Ca2+/calmodulin.
Targeting bromodomains: epigenetic readers of lysine acetylation
Recent progress in the development of bromodomain inhibitors is highlighted, and their potential applications in drug discovery are highlighted. Expand
The structure of P‐TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation
The structures of the CDK9/CycT1 and free cyclin T2 are determined to understand the regulation of a transcriptional CDK by its cognate cyclin and shows flexibility that may be important for the interaction of this region with HIV TAT and HEXIM. Expand
The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs
High-resolution x-ray structures of the human enzyme in complexes with risedronate and zoledronate, two of the leading N-BPs in clinical use, reveal the molecular binding characteristics of an important pharmacological target and provide a route for further optimization of these important drugs. Expand