The inner beta barrel (β-barrel) is in many cases stabilized by intricate salt-bridge networks.[10]Loops at the C-terminal ends of the β-barrel are responsible for catalytic activity[11][12] while N-terminal end loops are important for the stability of the TIM-barrels. Structural inserts ranging from extended loops to independent protein domains may be inserted in place of these loops or at the N-terminus/C-terminals. TIM barrels appear to have evolved through gene duplication and domain fusion events of half-barrel proteins,[13] with a majority of TIM barrels originating from a common ancestor. This led many TIM barrels to possess internal symmetries.[14] Further gene duplication events of this ancestral TIM barrel led to diverging enzymes possessing the functional diversity observed today. TIM barrels have also been a longstanding target for protein designers. Successful TIM barrel designs include both domain fusions of existing proteins and de novo designs. Domain fusions experiments have resulted in many successful designs,[15][16][17][18][19][20][21] whereas de novo designs only yielded successes after 28 years of incremental development.[22]
^Voet D, Voet JG (2011). "Chapter 8. Three-Dimensional Structures of Proteins". Biochemistry (4th ed.). John Wiley & Sons, Inc. ISBN978-0470-91745-9.
^Webb EC (1992). Enzyme nomenclature: Recommendations of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology on the Nomenclature and Classification of Enzymes. Academic Press. ISBN978-0-12-227164-9.
^Nagano N, Orengo CA, Thornton JM (August 2002). "One fold with many functions: the evolutionary relationships between TIM barrel families based on their sequences, structures and functions". Journal of Molecular Biology. 321 (5): 741–65. doi:10.1016/s0022-2836(02)00649-6. PMID12206759.
^Seitz T, Bocola M, Claren J, Sterner R (September 2007). "Stabilisation of a (βα)8-barrel protein designed from identical half barrels". Journal of Molecular Biology. 372 (1): 114–29. doi:10.1016/j.jmb.2007.06.036. PMID17631894.
^Höcker B, Lochner A, Seitz T, Claren J, Sterner R (February 2009). "High-resolution crystal structure of an artificial (βα)(8)-barrel protein designed from identical half-barrels". Biochemistry. 48 (6): 1145–7. doi:10.1021/bi802125b. PMID19166324.
^Eisenbeis S, Proffitt W, Coles M, Truffault V, Shanmugaratnam S, Meiler J, Höcker B (March 2012). "Potential of fragment recombination for rational design of proteins". Journal of the American Chemical Society. 134 (9): 4019–22. doi:10.1021/ja211657k. PMID22329686.