Protein Crystals as Novel Catalytic Materials

Abstract

In this era of molecular biology, protein crystallization is often considered to be a necessary first step in obtaining structural information through X‐ray diffraction analysis. In a different light, protein crystals can also be thought of as materials, whose chemical and physical properties make them broadly attractive and useful across a larger spectrum of disciplines. The full potential of these protein crystalline materials has been severely restricted in practice, however, both by their inherent fragility, and by strongly held skepticism concerning their routine and predictable growth, formulation, and practical application. Fortunately, these problems have turned out to be solvable. A systematic exploration of the biophysics and biochemistry of protein crystallization has shown that one can dependably create new protein crystalline materials more or less at will. In turn, these crystals can be readily strengthened, both chemically and mechanically, to make them suitable for practical commercialization. Today, these novel materials are used as industrial catalysts on a commercial scale, in bioremediation and “green chemistry” applications, and in enantioselective chromatography of pharmaceuticals and fine chemicals. In the near future, their utility will expand, to include the purification of protein drugs, formulation of direct protein therapeutics, and development of adjuvant‐less vaccines.

Crystal Polymorphism of Protein GB1 Examined by Solid-State NMR Spectroscopy and X-ray Diffraction

“…1,2 For example, formulation and cross-linking protocols resulted in increased enzymatic activity and substrate specificity of lipases. 1 Pharmaceutical applications of protein crystals benefit from higher concentrations, improved delivery pharmacokinetics, stability and versatility in routes of drug administration. [3][4][5] Insulin, perhaps the most famous therapeutic protein, has been used since 1922 to treat diabetic patients.…”

“…4,6 Microcrystalline precipitates of insulin provide a controlled release formulation that better mimics the properties of naturally secreted insulin. 3,5,7 Despite the great potential of protein crystallization, its application to other therapeutic proteins has so far been limited, 1,3,8 in part because many crystallization reagents are not fit for human consumption. Failure to identify effective batch-scale crystallization conditions within this limitation has hindered further use of this method to the expanding number of therapeutic proteins and industrial enzymes.…”

Computational design of a protein crystal

“…Protein and biopolymer crystals also have wide applicability to catalysis, therapeutic formulation, and biomaterials (12). However, the space group and local crystalline structure of biopolymer crystals are most often not at the control of the researcher and are only identified after extensive screening and optimization of conditions that yield a diffraction-quality crystal.…”

Crystalline monoclonal antibodies for subcutaneous delivery

“…Among Ϸ400 biopharmaceuticals that are either approved or in advanced clinical trials, there is only one product, insulin, that is produced and administered in crystalline form (4). Yet crystallization of macromolecule pharmaceuticals, particularly proteins, can offer significant advantages, such as high stability, streamlining of manufacturing, controlled release of activity, and high doses at the delivery site, which is especially attractive for mAb therapies (5)(6)(7). Although crystallization of full-length Abs has been a subject of significant interest for the last three decades, very few intact mAbs have ever been crystallized (8-10).…”