Perspectives

The main potential advantage of microgravity is the possibility of obtaining crystals that diffract to higher resolution or crystals that have more favorable morphology. This could be especially important in structure-based drug design. There is now a certain amount of evidence that crystal growth in microgravity can have beneficial effects on the size and intrinsic order of macromolecular crystals. In many cases, crystals obtained in space are larger, have lower mosaicity, and diffract to higher resolution than comparable crystals grown on Earth. However, space-based crystallization programs have been very limited in scope in terms of the total number of samples compared with the enormous reach of modern protein crystallography on Earth. In addition, space-based crystallization efforts have been carried out under extremely adverse conditions. However, despite the greatly increased sophistication of ground-based protein crystallization projects, the crystals of many important targets have suboptimal diffraction characteristics. Improvements in diffraction that move a system from the margins of structure determination (3.0 to 2.5 A) to well beyond that boundary will have a significant impact on the ability of the resulting structure to provide important insights into biological mechanisms.

If the protein or proteins being crystallized are soluble and relatively stable, there is little doubt that extensive experimental manipulation in the laboratory will eventually lead to better-diffracting crystals. However, it is very difficult to obtain membrane protein crystals that diffract to high resolution, so membrane proteins, such as the potassium channel, are attractive targets for investigation in microgravity. Potassium channels are integral membrane proteins that are important elements in the functioning of neuronal cells, and they also play diverse roles in the physiology of many different cell types. The potassium channels of greatest interest are those found in mammalian, particularly human, cells. However, it has not yet been possible to obtain crystals of mammalian potassium channels that are suitable for X-ray crystallographic analysis. There would be enormous value in improving the structural accuracy of the model for potassium channels (MacKinnon 2004).

Other proteins yielding crystals that diffract very poorly are those that form transient complexes during dynamic events, such as during cellular signaling. There is great interest in obtaining high-resolution structural analyses of such protein complexes, and these may benefit from the particular conditions of microgravity.

Drug design projects are another case where microgravity may be important. In the design of inhibitors it is usually important to see the stereochemistry by which binding occurs, and it is also necessary that the crystal structure be obtained for the precise target in question rather than for a closely related protein. This is a restriction that is usually avoided in practice, since the protein crystallographer will often search a set of closely related proteins for a protein with optimal crystallization characteristics. It is not at all uncommon to find that the particular protein that is most interesting, for example, the human variant of a family of proteins, does not yield suitable crystals.

The relatively poor diffraction obtained for such systems can arise for one or more reasons. These include the intrinsic flexibility of the macromolecular system being crystallized, as well as impurities or other factors that impede optimal crystal growth. At present there is no direct information on whether crystallization in microgravity will have a positive impact in cases where the sole inhibitor of crystallization is the intrinsic flexibility of the molecules involved. Further experimentation will help resolve this question, but the controlled manner in which crystals grow in microgravity may be beneficial in these cases.

Also, because protein crystals are up to 80% liquid, they can be used as a "sponge" to soak up drugs. After these crystals are injected into a patient, the drugs they embrace are released at a fairly constant rate as the crystal dissolves. This both extends the life of a single injection and eliminates or reduces the peaks and valleys of drug introduction, so harmful to those now undergoing drug treatment for diabetes and hepatitis.

Growing protein crystals in space helps to better understand their structure, as well as investigate their utility for a number of medical applications, such as a time-release vehicle for drugs (e.g., insulin and interferon). Although none of these protein crystals grown in space are ready for the market, several are undergoing clinical testing. However, there are around 100,000 protein crystals in the human body. Thus far, 2,000 structures have been defined. Importantly, new knowledge and techniques are increasing the effectiveness of protein crystallography through DNA studies and a number of related research efforts. Although it is certainly true that not all

Figure 8-11. Astronaut Sergei K. Krikalev, holds a sample tube within the Commercial Protein Crystallization

Facility-2 in the Zvezda Service Module of ISS. Photo courtesy of NASA.

Figure 8-11. Astronaut Sergei K. Krikalev, holds a sample tube within the Commercial Protein Crystallization

Facility-2 in the Zvezda Service Module of ISS. Photo courtesy of NASA.

protein crystals are of interest, and perhaps there are some which will resist crystallization, it seems there will be a continuous need for space-based research.

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