2KBU

NMR solution structure of Pin1 WW domain mutant with beta turn mimic at position 12

Summary for 2KBU

• Entry DOI: 10.2210/pdb2kbu/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (1 entity in total)
• Functional Keywords: beta sheet nucleator, beta turn mimic, cell cycle, isomerase, nucleus, phosphoprotein, rotamase
• Cellular location: Nucleus: Q13526
• Total number of polymer chains: 1
• Total formula weight: 3742.27

Authors

Fuller, A.A.,Bhabha, G.,Case, D.A. (deposition date: 2008-12-08, release date: 2009-07-07, Last modification date: 2024-07-10)

Primary citation

Fuller, A.A.,Du, D.,Liu, F.,Davoren, J.E.,Bhabha, G.,Kroon, G.,Case, D.A.,Dyson, H.J.,Powers, E.T.,Wipf, P.,Gruebele, M.,Kelly, J.W.
Evaluating beta-turn mimics as beta-sheet folding nucleators.
Proc.Natl.Acad.Sci.USA, 106:11067-11072, 2009

PubMed Abstract: 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.

PubMed: 19541614
DOI: 10.1073/pnas.0813012106

Experimental method

SOLUTION NMR