NanoRacks-Protein crystal growth in microgravity to enable therapeutic discovery (NanoRacks-PCG Therapeutic Discovery) - 07.20.16
Proteins are important biological molecules that can be crystallized to provide better views of their structure and function. Proteins crystallized in microgravity produce better-organized, larger crystals that are easier to study than those produced on Earth. NanoRacks-Protein Crystal Growth in Space to Enable Therapeutic Discovery (NanoRacks-PCG Therapeutic Discovery) tests whether microgravity improves the crystallization of two proteins that are important for future treatment of heart disease and cancer. Science Results for Everyone
Information Pending Experiment Details
OpNom: Module-19 S/N 1002
Brian Hubbard, Ph.D. , Broad Institute of MIT and Harvard, Cambridge, MA, United States
Matthew Clifton, United States
Cory Gerdts, Ph.D. , Protein BioSolutions, Gaithersburg, MD, United States
NanoRacks LLC, Webster, TX, United States
Sponsoring Space Agency
National Aeronautics and Space Administration (NASA)
National Laboratory (NL)
ISS Expedition Duration
September 2014 - March 2015
- Protein crystals grown in microgravity may produce larger, better-organized crystals that allow determination of more detailed structures that enable drug discovery and development studies. NanoRacks-Protein crystal growth in microgravity to enable therapeutic discovery (NanoRacks-PCG Therapeutic Discovery) seeks to obtain crystal structures of two challenging therapeutic targets, proprotein convertase subtilisin/kexin type 9 (PCSK9) and myeloid leukemia cell differentiation protein 1 (MCL1).
- The PCSK9 gene regulates cholesterol levels in the blood, and is one of the key genes that drive elevated levels of low-density lipoprotein (LDL) cholesterol. A therapy that successfully targets the PCSK9 protein and modulates LDL cholesterol would transform the treatment of coronary artery disease, one of the leading causes of death worldwide.
- Structures of PCSK9 have been solved in several different bound states, but often require the presence of a small peptide or an antibody. Having the ability to reliably grow crystals of PCSK9 in the absence of a binding partner (Apo-PCSK9) would be a major breakthrough for the structural biology of this target. Additionally, successful growth of Apo-PCSK9 crystals and structure determination enables the characterization of any small-molecule inhibitors of PCSK9 that emerge from therapeutic discovery efforts.
- MCL1 is one of the most commonly altered genes in cancer. It is linked to tumor development across a wide variety of cancer types, and is strongly implicated in chemotherapy resistance. These findings suggest that MCL1 is a highly attractive therapeutic target in cancer.
- Structures of MCL1 have been obtained in the presence of peptides as well as with small molecule inhibitors. However, neither the human or mouse forms of MCL1 have been solved by x-ray in their empty state (Apo-MCL1). Successful crystal growth and structural determination of Apo-MCL1 enables the characterization of any small-molecule inhibitors of MCL1 that emerge from therapeutic discovery efforts.
NanoRacks-Protein crystal growth in microgravity to enable therapeutic discovery (NanoRacks-PCG Therapeutic Discovery) explores the effects of microgravity on crystal growth of proprotein convertase subtilisin/kexin type 9 (PCSK9) and myeloid leukemia cell differentiation protein 1 (MCL1) proteins, through collaboration with the Broad Institute of MIT and Harvard, Beryllium, Protein BioSolutions and NanoRacks, initially in a two-phase experiment. In Phase 1 (pilot) NanoRacks-PCG Therapeutic Discovery assess growth of protein crystals in the specialized CrystalCards™, made by Protein BioSolutions, using a broad range of experimental conditions under normal gravity. Data from these experiments define the starting points for various conditions to explore in microgravity (Phase 2), and allow a “test run” of the hardware required to fill the CrystalCards™. In Phase 2 (production), NanoRacks-PCG Therapeutic Discovery focuses in on the conditions defined in the pilot phase for each protein, while still exploring a wide range of various conditions to optimize growth of quality crystals. To accurately assess the effects of microgravity, this phase is performed with a parallel control experiment run on earth, under normal gravity. The CrystalCards™ for the microgravity arm of the experiment are shipped to NanoRacks for loading onto the launch vehicle, transport to the International Space Station (ISS), and recovery. At the end of the production phase, crystal growth is evaluated and any crystals obtained (either in microgravity or on Earth) are submitted for data collection and structure determination. A modular experiment with two different protein constructs (one for PCSK9 and one for MCL1) is proposed to maximize the chance for success.
Protein crystals provide a 3-dimensional view of a protein’s structure and function, enabling scientists to understand how they work in the body. Some large proteins are difficult to crystallize, especially on Earth, where gravity interferes with their growth. The unique microgravity environment of the International Space Station enables the growth of large protein crystals that are relevant for drug development and other medical studies.
NanoRacks-PCG Therapeutic Discovery tests whether microgravity offers an ideal environment to crystallize two specific proteins, called proprotein convertase subtilisin/kexin type 9 (PCSK9) and myeloid leukemia cell differentiation protein 1 (MCL1). PCSK9 regulates cholesterol levels in the blood, and drugs that can target it would be important for treating coronary artery disease, a leading cause of death worldwide. MCL1 is one of the most common cancer-related genes, and is linked not only to tumor development but also resistance to chemotherapy. Improved crystals of these proteins enable researchers to find small molecules that can interact with the proteins, potentially leading to new drugs that can improve health and save lives.
Operational Requirements and Protocols
NanoRacks Module-19 is soft-stowed in a Glacier at -95°C. Crew removes the module from Glacier and places it inside NanoRacks Platform-1. Thaw and crystal growth occur without crew interaction. The crew observes crystal growth status on the slides.^ back to top
Decadal Survey Recommendations
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