Volume 537 Number 7618

Editorials

News

News Features

News & Views

Attack on amyloid-β protein p.36

An antibody therapy markedly reduces aggregates of amyloid-β, the hallmark protein of Alzheimer's disease, and might slow cognitive decline in patients. Confirmation of a cognitive benefit would be a game-changer. See Article p.50

doi: 10.1038/537036a

Cometary dust under the microscope p.37

The Rosetta spacecraft made history by successfully orbiting a comet. Data from the craft now reveal the structure of the comet's dust particles, shedding light on the processes that form planetary systems. See Letter p.73

doi: 10.1038/537037a

Moulding the ribosome p.38

Production of the cell's translational apparatus, the ribosome, requires the orchestrated function of hundreds of proteins. A structure of its earliest precursor yields unprecedented insight into ribosome formation.

doi: 10.1038/537038a

Southern Ocean freshened by sea ice p.40

The Southern Ocean has become less salty during the past few decades. An analysis of sea-ice transport in the ocean suggests that this phenomenon can be explained by coupled changes in sea-ice drift and thickness. See Letter p.89

doi: 10.1038/537040a

Suffocation of gene expression p.42

If a tumour outgrows its blood supply, oxygen levels in its cells decrease. It emerges that this change can alter gene expression by limiting the activity of TET enzymes, which remove methyl groups from DNA. See Article p.63

doi: 10.1038/nature19426

Muddy messages about American migration p.43

When and by which paths did early humans migrate into America? An analysis of ancient plant and animal remains revises the timeframe during which a route may have opened between ice sheets in northwest America. See Article p.45

doi: 10.1038/nature19421

Articles

Postglacial viability and colonization in North America’s ice-free corridor p.45

During much of the last ice age, continental ice sheets prevented humans from migrating into North America from Siberia; an environmental reconstruction of the corridor that opened up between the Cordilleran and Laurentide ice sheets reveals that it would have been inhospitable to the initial colonizing humans, who therefore probably entered North America by a different route.

doi: 10.1038/nature19085

Letters

A combined transmission spectrum of the Earth-sized exoplanets TRAPPIST-1 b and c p.69

Recently, temperate Earth-sized planets were discovered around the nearby star TRAPPIST-1; now, preliminary transmission spectra observations of the two inner planets by the Hubble Space Telescope suggest that these planets do not have a hydrogen-dominated atmosphere and are thus terrestrial, their atmospheric type still to be determined.

doi: 10.1038/nature18641

Ablation-cooled material removal with ultrafast bursts of pulses p.84

Ablation cooling is demonstrated as an effective means of removing material using successive bursts of laser pulses with short intraburst delay times; the technique allows the overall pulse energy to be decreased, overcoming negative thermal effects during the ablation process.

doi: 10.1038/nature18619

Addition of multiple limiting resources reduces grassland diversity p.93

Analysis of multi-year nutrient enrichment experiments carried out on 45 global grassland sites show that an addition of an increasing number of nutrients leads to a reduction in plant species diversity, and competition for multiple below-ground resources promotes plant species diversity.

doi: 10.1038/nature19324

Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala p.97

A brain circuit is identified through which serotonin induces an anxiety-like state; this circuit also mediates the anxiety-like behaviour induced by acute administration of the selective serotonin reuptake inhibitor fluoxetine and may underlie the early adverse events that some patients with anxiety disorders have to these types of drugs.

doi: 10.1038/nature19318

Structural basis for inhibition of a voltage-gated Ca2+ channel by Ca2+ antagonist drugs p.117

Ca2+ antagonist drugs are widely used in therapy of cardiovascular disorders. Three chemical classes of drugs bind to three separate, but allosterically interacting, receptor sites on CaV1.2 channels, the most prominent voltage-gated Ca2+ (CaV) channel type in myocytes in cardiac and vascular smooth muscle. The 1,4-dihydropyridines are used primarily for treatment of hypertension and angina pectoris and are thought to act as allosteric modulators of voltage-dependent Ca2+ channel activation, whereas phenylalkylamines and benzothiazepines are used primarily for treatment of cardiac arrhythmias and are thought to physically block the pore. The structural basis for the different binding, action, and therapeutic uses of these drugs remains unknown. Here we present crystallographic and functional analyses of drug binding to the bacterial homotetrameric model CaV channel CaVAb, which is inhibited by dihydropyridines and phenylalkylamines with nanomolar affinity in a state-dependent manner. The binding site for amlodipine and other dihydropyridines is located on the external, lipid-facing surface of the pore module, positioned at the interface of two subunits. Dihydropyridine binding allosterically induces an asymmetric conformation of the selectivity filter, in which partially dehydrated Ca2+ interacts directly with one subunit and blocks the pore. In contrast, the phenylalkylamine Br-verapamil binds in the central cavity of the pore on the intracellular side of the selectivity filter, physically blocking the ion-conducting pathway. Structure-based mutations of key amino-acid residues confirm drug binding at both sites. Our results define the structural basis for binding of dihydropyridines and phenylalkylamines at their distinct receptor sites on CaV channels and offer key insights into their fundamental mechanisms of action and differential therapeutic uses in cardiovascular diseases.

doi: 10.1038/nature19102