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The structure of acanthaporin, a neurotoxic and antimicrobial pore-forming protein from the pathogen Acanthamoeba culbertsoni reveals a currently unknown protein fold and a pH-dependent histidine switch that controls interconversion between the inactive dimer and the active monomer. Cover art by Erin Boyle, based on an image from Matthias Leippe. Article, p37
Public-private partnerships can reinvigorate precompetitive scientific research and de-risk drug discovery programs to help them meet demand for better and safer therapies.
Chemical probes are urgently needed to functionally annotate hitherto-untargeted kinases and stimulate new drug discovery efforts to address unmet medical needs. The size of the human kinome combined with the high cost associated with probe generation severely limits access to new probes. We propose a large-scale public-private partnership as a new approach that offers economies of scale, minimized redundancy and sharing of risk and cost.
Conformational targeting enabled the creation of a ubiquitin variant that specifically inhibits the deubiquitinating enzyme ubiquitin-specific protease 7 (also known as HAUSP). Generation of such tools is essential to unravel the complexities of ubiquitin signaling, but how general is this approach?
Aerobic inactivation of hydrogenases is a serious limitation to applications of the enzyme in biotechnology and has been extensively studied. A recent investigation combining electrochemical and spectroscopic methods shows that the molecular species that form as a result of exposure to O2 can be formed anaerobically and thus cannot involve incorporation of oxygen in the enzyme.
New, bioactive marine sponge compounds that function as inhibitors of the poly (ADP-ribose) polymerase family of proteins have now been identified to promote the correction of cystic fibrosis. Poly (ADP-ribose) polymerase inhibitors may be managers of proteostasis biology, consistent with their role (or roles) in remediation of inflammatory states.
Biotechnological applications of hydrogenases are limited by their susceptibility to inactivation by oxygen, thought to proceed by trapping a reduced O2 in the active site. Electrochemical and spectroscopic studies using various electron acceptors now show that oxygen inactivation is not linked to oxygen atom donation.
Selective 2′-hydroxyl acylation analyzed by primer extension (SHAPE) is a proven methodology for in vitro RNA secondary structure analysis. The identification of a new acylating agent permits the use of SHAPE to probe folded RNAs within living cells.
Medium-sized ring structures can provide unique entry points into natural product–like chemical space but are synthetically challenging to access. A biologically inspired method eases these challenges, employing a dearomatization-rearomatization sequence to form a diverse library of rings from tailored bicyclic compounds.
Equilibrium isomerization of retinol is a new activity now attributable to DES1. 11-cis-retinol synthesized by DES1 in Müller cells of the retina can be converted to the visual chromophore for regenerating opsin pigment in cone photoreceptors.
Acanthaporin is identified as a pore-forming protein from the infectious Acanthamoeba culbertsoni with a previously unknown structure. The newly identified structure includes a pH-dependent histidine switch that controls partitioning between the inactive dimer and the active monomer, which assembles into larger species to cause toxicity.
Src family kinase mutants, with altered regulatory domain interactions, were profiled with a photodependent crosslinking strategy to reveal conformation-specific ATP-competitive inhibitors that affect intermolecular binding interactions.
Stabilization of ubiquitin's β1-β2 region by computational design and phage display, targeting both buried and surface residues, yields a ubiquitin variant that specifically inhibits the deubiquitinase USP7 in vitro and in cells.
The human genome contains stretches of DNA sequence with unknown function. Peptidomics coupled to RNA-Seq now reveals a class of short open reading frames in human genomes that are translated into small peptides.