PDBsum entry 2kbu

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Isomerase PDB id
Protein chain
31 a.a.

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Key reference
Title Evaluating beta-Turn mimics as beta-Sheet folding nucleators.
Authors A.A.Fuller, D.Du, F.Liu, J.E.Davoren, G.Bhabha, G.Kroon, D.A.Case, H.J.Dyson, E.T.Powers, P.Wipf, M.Gruebele, J.W.Kelly.
Ref. Proc Natl Acad Sci U S A, 2009, 106, 11067-11072. [DOI no: 10.1073/pnas.0813012106]
PubMed id 19541614
Beta-turns are common conformations that enable proteins to adopt globular structures, and their formation is often rate limiting for folding. Beta-turn mimics, molecules that replace the i + 1 and i + 2 amino acid residues of a beta-turn, are envisioned to act as folding nucleators by preorganizing the pendant polypeptide chains, thereby lowering the activation barrier for beta-sheet formation. However, the crucial kinetic experiments to demonstrate that beta-turn mimics can act as strong nucleators in the context of a cooperatively folding protein have not been reported. We have incorporated 6 beta-turn mimics simulating varied beta-turn types in place of 2 residues in an engineered beta-turn 1 or beta-bulge turn 1 of the Pin 1 WW domain, a three-stranded beta-sheet protein. We present 2 lines of kinetic evidence that the inclusion of beta-turn mimics alters beta-sheet folding rates, enabling us to classify beta-turn mimics into 3 categories: those that are weak nucleators but permit Pin WW folding, native-like nucleators, and strong nucleators. Strong nucleators accelerate folding relative to WW domains incorporating all alpha-amino acid sequences. A solution NMR structure reveals that the native Pin WW beta-sheet structure is retained upon incorporating a strong E-olefin nucleator. These beta-turn mimics can now be used to interrogate protein folding transition state structures and the 2 kinetic analyses presented can be used to assess the nucleation capacity of other beta-turn mimics.
Figure 1.
β-Turn mimics studied.
Figure 2.
Comparison of the solution structures of the Pin1 WW domain. (A) Superposition of 12 structures of the WT protein (36; PDB ID code 2kcf) (B) Superposition of 15 structures of variant C-4 (PDB ID code 2kbu). (C) Superposition of a low-energy structure from each of the ensembles in (A) and (B). The inset shows the structure of dipeptide replacement 4 in loop 1.
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