P41GM139687

Structural Dynamics at LCLS - Abstract:

Overall, the goal of this proposal is to form a Biomedical Technology Research Resource (BTRR) at SLAC National Accelerator Laboratory that involves a set of interrelated Technology Research and Development (TR&D) projects aimed at enhancing and developing the unique capabilities of the SLAC Linac Coherent Light Source (LCLS) for biomedical applications.

The BTRR will enable structural biology experiments that are extremely difficult or impossible to perform at synchrotron (SR) or electron microscopy (cryoEM) facilities and will increase the availability of these capabilities to the broader structural biology community. The enabled experiments will facilitate paradigm-shifting advances on a wide variety of topics, including neurotransmission, signal transduction, cellular metabolism, transcription, and viral infection.

The proposed TR&Ds are tightly coupled with the research themes of the nine driving biomedical projects (DBPs). These research themes focus on developments to visualize large complexes and membrane proteins, such as GPCRs, and provide accurate active site structures of metalloenzymes, such as ribonucleotide reductase and cytochrome c oxidase, and complex macromolecular machines, such as RNA polymerase-II. Finally, a common research area of all DBPs involves time-resolved (TR) studies that include research to follow dynamic processes involved in adenine riboswitch signaling, the transport mechanism of N. gonorrhoeae MtrF, antibiotic binding to SS-lactamase, and examination of interaction specificity of CypA variants.

All DBPs hinge on highly efficient data collection methods, which are required for successful macromolecular crystallography (MC) experiments at X-ray FELs. The high peak brightness of an X-ray FEL pulse destroys the crystal volume exposed, bringing about sample refreshment challenges previously unknown to the MC SR community. As a result, the sample must be continually replenished throughout the experiment.

As part of the TR&Ds, sample injectors that rapidly deliver crystals and sample solutions to the X-ray beam will be optimized and automated during LCLS experiments, along with data analysis to gauge experimental success and optimize the use of limited sample and beam time. Time-resolved studies hinge on improvements to mixing injectors, laser activation, and complementary spectroscopic methods.

X-ray FEL beam time is scarce, so careful characterization of samples and complex experimental setups prior to beam time is critical to ensure experimental success, in particular for complex time-resolved measurements of sensitive metalloenzyme intermediates. Experimental design and testing, sample production, sample characterization (including spectroscopic analysis), and crystal quality screening are supported in the laboratory, at the Stanford Synchrotron Radiation Lightsource (SSRL), and during screening beam time at LCLS.

Integrating with and enhancing the existing programs at SSRL and LCLS, the BTRR will provide support, expertise, and training to the biomedical community.

The Leland Stanford Junior University

THE NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES (NIGMS) SUPPORTS BASIC RESEARCH THAT INCREASES OUR UNDERSTANDING OF BIOLOGICAL PROCESSES AND LAYS THE FOUNDATION FOR ADVANCES IN DISEASE DIAGNOSIS, TREATMENT, AND PREVENTION. NIGMS ALSO SUPPORTS RESEARCH IN SPECIFIC CLINICAL AREAS THAT AFFECT MULTIPLE ORGAN SYSTEMS: ANESTHESIOLOGY AND PERI-OPERATIVE PAIN, CLINICAL PHARMACOLOGY ?COMMON TO MULTIPLE DRUGS AND TREATMENTS, AND INJURY, CRITICAL ILLNESS, SEPSIS, AND WOUND HEALING.? NIGMS-FUNDED SCIENTISTS INVESTIGATE HOW LIVING SYSTEMS WORK AT A RANGE OF LEVELSFROM MOLECULES AND CELLS TO TISSUES AND ORGANSIN RESEARCH ORGANISMS, HUMANS, AND POPULATIONS. ADDITIONALLY, TO ENSURE THE VITALITY AND CONTINUED PRODUCTIVITY OF THE RESEARCH ENTERPRISE, NIGMS PROVIDES LEADERSHIP IN SUPPORTING THE TRAINING OF THE NEXT GENERATION OF SCIENTISTS, ENHANCING THE DIVERSITY OF THE SCIENTIFIC WORKFORCE, AND DEVELOPING RESEARCH CAPACITY THROUGHOUT THE COUNTRY.

93.859 - Biomedical Research and Research Training

National Institute of General Medical Sciences (NIGMS) [HHS - NIH]

California United States

State-Wide

Biomedical Technology Research Resource (P41) (PAR-17-316)

Amendment Since initial award the total obligations have increased 372% from $1,594,586 to $7,526,067.