[ASAP] Thermally versus Chemically Denatured Protein States

May 15th, 2019 by Abhishek Narayan, Kabita Bhattacharjee, Athi N. Naganathan

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Biochemistry
DOI: 10.1021/acs.biochem.9b00089

MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition

May 13th, 2019 by Rebecca C. Coll

MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition

Nature Chemical Biology, Published online: 13 May 2019; doi:10.1038/s41589-019-0277-7

MCC950, a small-molecule inhibitor of the NLRP3 inflammasome, interacts directly with NLRP3 at the Walker B motif that hydrolyzes ATP, as defined by a protease-susceptibility assay, mutational analysis, and surface plasmon resonance analysis.
  • Posted in Nat Chem Biol, Publications
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Substrate-selective inhibitors that reprogram the activity of insulin-degrading enzyme

May 13th, 2019 by Juan Pablo Maianti

Substrate-selective inhibitors that reprogram the activity of insulin-degrading enzyme

Nature Chemical Biology, Published online: 13 May 2019; doi:10.1038/s41589-019-0271-0

High-throughput screening identifies compounds that target insulin-degrading enzyme (IDE) and X-ray co-crystallography reveals how these compounds block insulin degradation by IDE but support its proteolysis of other substrates, including glucagon.
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Author Correction: In-solution enrichment identifies peptide inhibitors of protein–protein interactions

May 13th, 2019 by Fayçal Touti

Author Correction: In-solution enrichment identifies peptide inhibitors of protein–protein interactions

Nature Chemical Biology, Published online: 13 May 2019; doi:10.1038/s41589-019-0302-x

Author Correction: In-solution enrichment identifies peptide inhibitors of protein–protein interactions
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Walking over the inflammasome

May 13th, 2019 by Oliver Gorka

Walking over the inflammasome

Nature Chemical Biology, Published online: 13 May 2019; doi:10.1038/s41589-019-0292-8

The NLRP3 inflammasome contributes to pathogenic inflammation in a broad range of diseases, making it a highly relevant drug target. Two studies published in this issue found an inhibitor of NLRP3 inflammasome activation to directly bind NLRP3 within its central NACHT domain, interfering with ATP hydrolysis and structural changes critical for NLRP3 oligomerization and subsequent inflammasome formation.

MCC950 closes the active conformation of NLRP3 to an inactive state

May 13th, 2019 by Ana Tapia-Abellán

MCC950 closes the active conformation of NLRP3 to an inactive state

Nature Chemical Biology, Published online: 13 May 2019; doi:10.1038/s41589-019-0278-6

MCC950, a small-molecule inhibitor of the NLRP3 inflammasome, inactivates NLRP3, including hyperactive disease-linked mutations, by closing the ‘open’ conformation, thereby preventing conformational changes required for NLRP3 activation.

Light-based control of metabolic flux through assembly of synthetic organelles

May 13th, 2019 by Evan M. Zhao

Light-based control of metabolic flux through assembly of synthetic organelles

Nature Chemical Biology, Published online: 13 May 2019; doi:10.1038/s41589-019-0284-8

Optogenetically controlling the assembly of enzyme clusters enhances product formation and specificity during deoxyviolacein biosynthesis by decreasing concentrations of intermediate metabolites and reducing flux through competing pathways.
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[ASAP] Elucidating the Determinants of Polymerase Specificity by Microfluidic-Based Deep Mutational Scanning

May 12th, 2019 by Ali Nikoomanzar, Derek Vallejo, John C. Chaput

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ACS Synthetic Biology
DOI: 10.1021/acssynbio.9b00104
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Face-time with TAR: Portraits of an HIV-1 RNA with diverse modes of effector recognition relevant for drug discovery [RNA]

May 12th, 2019 by Sai Shashank Chavali, Rachel Bonn-Breach, Joseph E. Wedekind

Small molecules and short peptides that potently and selectively bind RNA are rare, making the molecular structures of these complexes highly exceptional. Accordingly, several recent investigations have provided unprecedented structural insights into how peptides and proteins recognize the HIV-1 trans-activation response (TAR) element, a 59-nucleotide long, noncoding RNA segment in the 5'-long terminal repeat region of viral transcripts. Here we offer an integrated perspective on these advances by describing earlier progress on TAR-binding to small molecules, and by drawing parallels to recent successes in the identification of compounds that target the hepatitis C virus internal ribosome entry site (IRES) and the flavin-mononucleotide riboswitch. We relate this work to recent progress that pinpoints specific determinants of TAR recognition by: (i) viral Tat proteins, (ii) an innovative lab-evolved TAR-binding protein and (iii) an ultrahigh-affinity cyclic peptide. New structural details are used to model the TAR-Tat-super elongation complex (SEC) that is essential for efficient viral transcription and represents a focal point for antiviral drug design. A key prediction is that the Tat transactivation domain makes modest contacts with the TAR apical loop, whereas its arginine-rich motif (ARM) spans the entire length of the TAR major groove. This expansive interface has significant implications for drug discovery and design, and further suggests that future lab-evolved proteins could be deployed to discover steric restriction points that block Tat-mediated recruitment of the host SEC to HIV-1 TAR.

Author Correction: Affinity-based capture and identification of protein effectors of the growth regulator ppGpp

May 10th, 2019 by Boyuan Wang

Author Correction: Affinity-based capture and identification of protein effectors of the growth regulator ppGpp

Nature Chemical Biology, Published online: 10 May 2019; doi:10.1038/s41589-019-0296-4

Author Correction: Affinity-based capture and identification of protein effectors of the growth regulator ppGpp
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