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Combining large scale in silico analysis with fragment screening to identify novel, ligandable secondary sites in cancer-associated proteins
(Institute of Cancer Research (University Of London), 2020-01-31)
Proteins often have multiple binding sites involved in interactions with other molecules. The majority of currently approved drugs bind a protein's primary site, the major functional site in the protein. Targeting the ...
Structures of APC/C(Cdh1) with substrates identify Cdh1 and Apc10 as the D-box co-receptor.
(NATURE PUBLISHING GROUP, 2011-02-10)
The ubiquitylation of cell-cycle regulatory proteins by the large multimeric anaphase-promoting complex (APC/C) controls sister chromatid segregation and the exit from mitosis. Selection of APC/C targets is achieved through ...
Three-dimensional structure of recombinant type 1 inositol 1,4,5-trisphosphate receptor.
(PORTLAND PRESS LTD, 2010-05-27)
IP3Rs (inositol 1,4,5-trisphosphate receptors) are the intracellular channels that mediate release of Ca2+ from the endoplasmic reticulum in response to the many stimuli that evoke Ins(1,4,5)P3 formation. We characterized ...
Hybrid Gene Origination Creates Human-Virus Chimeric Proteins during Infection.
(CELL PRESS, 2020-06-25)
RNA viruses are a major human health threat. The life cycles of many highly pathogenic RNA viruses like influenza A virus (IAV) and Lassa virus depends on host mRNA, because viral polymerases cleave 5'-m7G-capped host ...
Prereplicative complexes assembled in vitro support origin-dependent and independent DNA replication.
(WILEY-BLACKWELL, 2014-03-18)
Eukaryotic DNA replication initiates from multiple replication origins. To ensure each origin fires just once per cell cycle, initiation is divided into two biochemically discrete steps: the Mcm2-7 helicase is first loaded ...
Structural basis for translocation by AddAB helicase-nuclease and its arrest at χ sites.
(NATURE PUBLISHING GROUP, 2014-04-17)
In bacterial cells, processing of double-stranded DNA breaks for repair by homologous recombination is dependent upon the recombination hotspot sequence χ (Chi) and is catalysed by either an AddAB- or RecBCD-type ...
Origin licensing requires ATP binding and hydrolysis by the MCM replicative helicase.
(CELL PRESS, 2014-09-04)
Loading of the six related Minichromosome Maintenance (MCM) proteins as head-to-head double hexamers during DNA replication origin licensing is crucial for ensuring once-per-cell-cycle DNA replication in eukaryotic cells. ...
Structural and functional characterization of the human and yeast TFIIIC complex
(Institute of Cancer Research (University Of London), 2019-11-30)
TFIIIC is one of the conserved transcription factors required for RNA Polymerase (Pol) III transcription, which transcribes DNA into untranslated RNAs, such as tRNAs. However, TFIIIC's mechanistic role in Pol III regulation ...
A closed conformation of the Caenorhabditis elegans separase-securin complex.
(ROYAL SOC, 2016-04-13)
The protease separase plays a key role in sister chromatid disjunction and centriole disengagement. To maintain genomic stability, separase activity is strictly regulated by binding of an inhibitory protein, securin. Despite ...
Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737).
(AMER CHEMICAL SOC, 2016-06-09)
Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy ...