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 similar to 20 degrees 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.

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

Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein.

/pdf/androgen-receptor-structure-role-in-prostate-cancer-and-drug-4hfptgb67m.pdf

Androgen receptor: structure, role in prostate cancer and drug discovery

A Perspective is presented on the history and current understanding of molecular gels and the factors that must be considered to characterize them. The abilities of the most important structural, dynamic, and rheological tools available currently to provide the information necessary to follow the formation of a molecular gel from its initial sol phase and then to define it at different distance and time scales are discussed. Approaches to determining a priori when a molecule will gelate a selected liquid, as well as possible methodologies for overcoming current limitations in understanding molecular gels, are presented. Finally, some of the many potential and realized applications for these materials are enumerated.

The past, present, and future of molecular gels. What is the status of the field, and where is it going?

Oxygen, which supports all aerobic life, is produced by photosynthetic water oxidation in plants, algae, and cyanobacteria. The water-oxidation reaction probably first appeared in nature ∼3 billion years ago in the precursors to present-day cyanobacteria, although the exact timing is not yet entirely clear.1−5 A key component in the appearance of oxygenic photosynthesis was a metal complex that could store oxidizing equivalents to facilitate the four-electron oxidation of two water molecules to dioxygen, meanwhile making the electrons available for the reductive carbon-fixing reactions required for sustaining life.6−8 This metal complex involved in oxygenic photosynthesis, the oxygen-evolving complex (OEC), consists of an oxo-bridged structure with four Mn atoms and one Ca atom. No variations have been observed so far among oxygenic photosynthetic organisms through higher plants and algae back to cyanobacteria, which represents the earliest oxygenic photosynthetic organisms. Oxygen itself is the byproduct of the photosynthetic water oxidation reaction shown in eq 1:




1


However, it was this oxygen that enabled oxygenic life to evolve and that led to the current diverse and complex life on earth by dramatically increasing the metabolic energy that became available from aerobic respiration. Oxygen produced by this process was also key for the development of the protective ozone layer, which allowed life to transition from marine forms to terrestrial life.

Mn4Ca Cluster in Photosynthesis: Where and How Water is Oxidized to Dioxygen

Lipidic cubic phase (LCP) crystallization has proven successful for high-resolution structure determination of challenging membrane proteins. Here we present a technique for extruding gel-like LCP ...

/pdf/lipidic-cubic-phase-injector-facilitates-membrane-protein-42khyi5g3v.pdf

Lipidic cubic phase injector facilitates membrane protein serial femtosecond crystallography

Structure determination of proteins and other macromolecules has historically required the growth of high-quality crystals sufficiently large to diffract x-rays efficiently while withstanding radiation damage. We applied serial femtosecond crystallography (SFX) using an x-ray free-electron laser (XFEL) to obtain high-resolution structural information from microcrystals (less than 1 micrometer by 1 micrometer by 3 micrometers) of the well-characterized model protein lysozyme. The agreement with synchrotron data demonstrates the immediate relevance of SFX for analyzing the structure of the large group of difficult-to-crystallize molecules.

/pdf/high-resolution-protein-structure-determination-by-serial-57uhykul5g.pdf

High-Resolution Protein Structure Determination by Serial Femtosecond Crystallography

Recent research has focused on developing techniques that use digital signal processors (DSPs) and field-programmable gate arrays (FPGAs) to support real-time simulation with frame times of a few microseconds or less. These techniques can be used to simulate, for example, modern power electronic systems in real time. Using these techniques as part of a larger system simulation with a wide dynamic bandwidth presents a number of challenges. Multirate solutions are often required, in which different frame times are used for different parts of the system. It is not normally a feasible option to implement the entire multi-rate simulation on a DSP-based or FPGA-based processor. Consequently the high-speed simulation must be integrated into a more conventional real-time simulation system, which is typically a real-time Linux-based system. The paper discusses some of the challenges involved in implementing an integrated high-speed, real-time, multi-rate simulation system.

W. Ghonsalves

Papers

High-Resolution Protein Structure Determination by Serial Femtosecond Crystallography

High-speed real-time multi-rate simulation

A multi-input multi-output self tuning regulator for nonlinear high performance aircraft control