2F21

human Pin1 Fip mutant

Summary for 2F21

• Entry DOI: 10.2210/pdb2f21/pdb
• Related: 1zcn
• Descriptor: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, PENTAETHYLENE GLYCOL (3 entities in total)
• Functional Keywords: ww domain, beta-sheet, isomerase
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: Q13526
• Total number of polymer chains: 1
• Total formula weight: 18602.68

Authors

Jager, M.,Zhang, Y.,Bowman, M.E.,Noel, J.P.,Kelly, J.W. (deposition date: 2005-11-15, release date: 2006-06-20, Last modification date: 2023-08-23)

Primary citation

Jager, M.,Zhang, Y.,Bieschke, J.,Nguyen, H.,Dendle, M.,Bowman, M.E.,Noel, J.P.,Gruebele, M.,Kelly, J.W.
Structure-function-folding relationship in a WW domain.
Proc.Natl.Acad.Sci.Usa, 103:10648-10653, 2006

PubMed Abstract: Protein folding barriers result from a combination of factors including unavoidable energetic frustration from nonnative interactions, natural variation and selection of the amino acid sequence for function, and/or selection pressure against aggregation. The rate-limiting step for human Pin1 WW domain folding is the formation of the loop 1 substructure. The native conformation of this six-residue loop positions side chains that are important for mediating protein-protein interactions through the binding of Pro-rich sequences. Replacement of the wild-type loop 1 primary structure by shorter sequences with a high propensity to fold into a type-I' beta-turn conformation or the statistically preferred type-I G1 bulge conformation accelerates WW domain folding by almost an order of magnitude and increases thermodynamic stability. However, loop engineering to optimize folding energetics has a significant downside: it effectively eliminates WW domain function according to ligand-binding studies. The energetic contribution of loop 1 to ligand binding appears to have evolved at the expense of fast folding and additional protein stability. Thus, the two-state barrier exhibited by the wild-type human Pin1 WW domain principally results from functional requirements, rather than from physical constraints inherent to even the most efficient loop formation process.

PubMed: 16807295
DOI: 10.1073/pnas.0600511103

Experimental method

X-RAY DIFFRACTION (1.5 Å)