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Designing protein function – Macromolecular design
Journal of Structural Biology 185 (2014) 135
Contents lists available at ScienceDirect
Journal of Structural Biology journal homepage: www.elsevier.com/locate/yjsbi
Editorial
Designing protein function – Macromolecular design
Structural biology has opened our eyes to the incredible diversity of macromolecular structures since their determination by X-ray crystallography became possible 50 years ago. The number of available protein structures increases exponentially and, concomitantly, our understanding of structure–function relationships has steadily improved. This rich source of knowledge has led the field beyond discovery and inspection of existing structures toward the design of proteins with new and improved functions. The functions targeted by design range from interactions with other macromolecules, with a strong focus on protein–protein interactions, to the recognition of molecules as small as metals or sugars. These interactions can result in inhibition or modulation of functions that are critical to cellular survival, such as signaling cascades or catalytic turnover. The range of interactions is part of the challenge for the protein design field. Small molecules are less complex and sometimes less flexible than large ones, but they have fewer contacts with the protein and thus provide fewer handles to optimize interactions. The large interfaces of protein–protein or protein–peptide interactions, in contrast, allow for many contacts, but require the handling of a very complex and often flexible interface. Beyond interactions, the design of enzymatic catalysis requires an even more detailed understanding of the mechanisms involved and precise positioning of chemically active moieties. A number of methods for the design of protein functions have emerged over the past 20 years. Many approaches involve computational analysis and modeling of the protein structure. Wet-lab techniques such as directed evolution, library construction, and high throughput screening often complement these computational methods, but can also be used on their own. This special issue on the design of protein function discusses current approaches and results. The topics range from computational methods for the design of non-natural interactions to the specific design challenges for pathway engineering. Several focus
1047-8477/$ - see front matter Ó 2014 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jsb.2014.01.011
points emerged, such as the engineering of protein–protein and protein–peptide interactions, the rational design of binding sites for metal and other small molecules, and intense efforts in antibody engineering due to medical and biotechnological applications. Another aspect that surfaces in many of the works and is the main aim in others is protein stability. A protein’s function is dependent on its structural stability; therefore, protein stability constitutes a crucial objective in many designs. An even increased interest in fine-tuning of protein stability can come from such different objectives as industrial processability or regulation of cellular pathways. Overall, we note that functional protein design has used its observational beginnings to launch into the engineering and design with structure to guide most of the way. Although facile and quick protein design is still a long way off, the past decade offers real benchmarks of progress. Protein-small molecule, protein–peptide, and protein–protein recognition are now attainable through redesign of current proteins. Structure-based protein design has become an established research field that promises robust use and interesting applications for the near future. We look forward to further exciting progress in this challenging research area, and hope that you enjoy reading about current views and recent results in this issue on the design of protein function. Birte Höcker Max Planck Institute for Developmental Biology, Spemannstr. 35, 72076 Tübingen, Germany E-mail address: [email protected] Katarina Midelfort Milwaukee School of Engineering, Physics and Chemistry Department, 1025 N Broadway, Milwaukee, WI 53202, USA E-mail address: [email protected]
Contents lists available at ScienceDirect
Journal of Structural Biology journal homepage: www.elsevier.com/locate/yjsbi
Editorial
Designing protein function – Macromolecular design
Structural biology has opened our eyes to the incredible diversity of macromolecular structures since their determination by X-ray crystallography became possible 50 years ago. The number of available protein structures increases exponentially and, concomitantly, our understanding of structure–function relationships has steadily improved. This rich source of knowledge has led the field beyond discovery and inspection of existing structures toward the design of proteins with new and improved functions. The functions targeted by design range from interactions with other macromolecules, with a strong focus on protein–protein interactions, to the recognition of molecules as small as metals or sugars. These interactions can result in inhibition or modulation of functions that are critical to cellular survival, such as signaling cascades or catalytic turnover. The range of interactions is part of the challenge for the protein design field. Small molecules are less complex and sometimes less flexible than large ones, but they have fewer contacts with the protein and thus provide fewer handles to optimize interactions. The large interfaces of protein–protein or protein–peptide interactions, in contrast, allow for many contacts, but require the handling of a very complex and often flexible interface. Beyond interactions, the design of enzymatic catalysis requires an even more detailed understanding of the mechanisms involved and precise positioning of chemically active moieties. A number of methods for the design of protein functions have emerged over the past 20 years. Many approaches involve computational analysis and modeling of the protein structure. Wet-lab techniques such as directed evolution, library construction, and high throughput screening often complement these computational methods, but can also be used on their own. This special issue on the design of protein function discusses current approaches and results. The topics range from computational methods for the design of non-natural interactions to the specific design challenges for pathway engineering. Several focus
1047-8477/$ - see front matter Ó 2014 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jsb.2014.01.011
points emerged, such as the engineering of protein–protein and protein–peptide interactions, the rational design of binding sites for metal and other small molecules, and intense efforts in antibody engineering due to medical and biotechnological applications. Another aspect that surfaces in many of the works and is the main aim in others is protein stability. A protein’s function is dependent on its structural stability; therefore, protein stability constitutes a crucial objective in many designs. An even increased interest in fine-tuning of protein stability can come from such different objectives as industrial processability or regulation of cellular pathways. Overall, we note that functional protein design has used its observational beginnings to launch into the engineering and design with structure to guide most of the way. Although facile and quick protein design is still a long way off, the past decade offers real benchmarks of progress. Protein-small molecule, protein–peptide, and protein–protein recognition are now attainable through redesign of current proteins. Structure-based protein design has become an established research field that promises robust use and interesting applications for the near future. We look forward to further exciting progress in this challenging research area, and hope that you enjoy reading about current views and recent results in this issue on the design of protein function. Birte Höcker Max Planck Institute for Developmental Biology, Spemannstr. 35, 72076 Tübingen, Germany E-mail address: [email protected] Katarina Midelfort Milwaukee School of Engineering, Physics and Chemistry Department, 1025 N Broadway, Milwaukee, WI 53202, USA E-mail address: [email protected]