Structural basis for bifunctional peptide recognition at human δ-opioid receptor

Bi-functional μ- and δ- opioid receptor (OR) ligands are potential therapeutic alternatives to alkaloid opiate analgesics with diminished side effects. We solved the structure of human δ-OR bound to the bi-functional δ-OR antagonist and μ-OR agonist tetrapeptide H-Dmt(1)-Tic(2)-Phe(3)-Phe(4)-NH2 (DIPP-NH2) by serial femtosecond crystallography, revealing a cis-peptide bond between H-Dmt(1) and Tic(2). The observed receptor-peptide interactions are critical to understand the pharmacological profiles of opioid peptides, and to develop improved analgesics

2014-2015 Master Class - James Dunham (Viola)

https://spiral.lynn.edu/conservatory_masterclasses/1026/thumbnail.jp

Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser.

G-protein-coupled receptors (GPCRs) signal primarily through G proteins or arrestins. Arrestin binding to GPCRs blocks G protein interaction and redirects signalling to numerous G-protein-independent pathways. Here we report the crystal structure of a constitutively active form of human rhodopsin bound to a pre-activated form of the mouse visual arrestin, determined by serial femtosecond X-ray laser crystallography. Together with extensive biochemical and mutagenesis data, the structure reveals an overall architecture of the rhodopsin-arrestin assembly in which rhodopsin uses distinct structural elements, including transmembrane helix 7 and helix 8, to recruit arrestin. Correspondingly, arrestin adopts the pre-activated conformation, with a ∼20° rotation between the amino and carboxy domains, which opens up a cleft in arrestin to accommodate a short helix formed by the second intracellular loop of rhodopsin. This structure provides a basis for understanding GPCR-mediated arrestin-biased signalling and demonstrates the power of X-ray lasers for advancing the frontiers of structural biology

Reimagining the potential of Earth observations for ecosystem service assessments

The benefits nature provides to people, called ecosystem services, are increasingly recognized and accounted for in assessments of infrastructure development, agricultural management, conservation prioritization, and sustainable sourcing. These assessments are often limited by data, however, a gap with tremendous potential to be filled through Earth observations (EO), which produce a variety of data across spatial and temporal extents and resolutions. Despite widespread recognition of this potential, in practice few ecosystem service studies use EO. Here, we identify challenges and opportunities to using EO in ecosystem service modeling and assessment. Some challenges are technical, related to data awareness, processing, and access. These challenges require systematic investment in model platforms and data management. Other challenges are more conceptual but still systemic; they are byproducts of the structure of existing ecosystem service models and addressing them requires scientific investment in solutions and tools applicable to a wide range of models and approaches. We also highlight new ways in which EO can be leveraged for ecosystem service assessments, identifying promising new areas of research. More widespread use of EO for ecosystem service assessment will only be achieved if all of these types of challenges are addressed. This will require non-traditional funding and partnering opportunities from private and public agencies to promote data exploration, sharing, and archiving. Investing in this integration will be reflected in better and more accurate ecosystem service assessments worldwide

Rapid sample delivery for megahertz serial crystallography at X-ray FELs

Liquid microjets are a common means of delivering protein crystals to the focus of X-ray free-electron lasers (FELs) for serial femtosecond crystallography measurements. The high X-ray intensity in the focus initiates an explosion of the microjet and sample. With the advent of X-ray FELs with megahertz rates, the typical velocities of these jets must be increased significantly in order to replenish the damaged material in time for the subsequent measurement with the next X-ray pulse. This work reports the results of a megahertz serial diffraction experiment at the FLASH FEL facility using 4.3 nm radiation. The operation of gas-dynamic nozzles that produce liquid microjets with velocities greater than 80 m s-1 was demonstrated. Furthermore, this article provides optical images of X-ray-induced explosions together with Bragg diffraction from protein microcrystals exposed to trains of X-ray pulses repeating at rates of up to 4.5 MHz. The results indicate the feasibility for megahertz serial crystallography measurements with hard X-rays and give guidance for the design of such experiments