PDBsum entry 1zcn

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Isomerase PDB id
Protein chain
143 a.a. *
1PE ×2
Waters ×110
* Residue conservation analysis
PDB id:
Name: Isomerase
Title: Human pin1 ng mutant
Structure: Peptidyl-prolyl cis-trans isomerase nima- interacting 1. Chain: a. Synonym: rotamase pin1, ppiase pin1. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pin1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
1.90Å     R-factor:   0.226     R-free:   0.269
Authors: M.Jager,Y.Zhang,H.Nguyen,G.Dendel,M.E.Bowman,M.Gruebele, J.P.Noel,J.W.Kelly
Key ref:
M.Jäger et al. (2006). Structure-function-folding relationship in a WW domain. Proc Natl Acad Sci U S A, 103, 10648-10653. PubMed id: 16807295 DOI: 10.1073/pnas.0600511103
12-Apr-05     Release date:   20-Jun-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q13526  (PIN1_HUMAN) -  Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1
163 a.a.
143 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - Peptidylprolyl isomerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Peptidylproline (omega=180) = peptidylproline (omega=0)
Peptidylproline (omega=180)
= peptidylproline (omega=0)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     midbody   5 terms 
  Biological process     metabolic process   15 terms 
  Biochemical function     protein binding     7 terms  


    Added reference    
DOI no: 10.1073/pnas.0600511103 Proc Natl Acad Sci U S A 103:10648-10653 (2006)
PubMed id: 16807295  
Structure-function-folding relationship in a WW domain.
M.Jäger, Y.Zhang, J.Bieschke, H.Nguyen, M.Dendle, M.E.Bowman, J.P.Noel, M.Gruebele, J.W.Kelly.
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.
  Selected figure(s)  
Figure 1.
Fig. 1. Loop structures and sequences of WW domains. (a) Backbone diagram of the loop 1 substructure in WT Pin WW (residues S16–R21) [Protein Data Bank (PDB) ID code 1PIN]. (b) Backbone diagram of the loop 1 substructure in WT FBP WW (residues T13–K17) (PDB ID code 1E01). Backbone H-bonds are indicated by black dotted lines. (c) Aligned sequences of the WT Pin WW domain (variant 1) and loop 1 redesigned variants 2–9 and the redesigned and sequence-minimized FBP WW variants (10 and 11). -strand residues are colored blue, residues that were mutated or deleted upon loop 1 redesign are in red, and all other residues are in gray.
Figure 3.
Fig. 3. Effect of loop 1 redesign on WW domain stability. (a) Normalized equilibrium unfolding transitions for Pin WW (variant 1) and variants 2–6 with either a confirmed (2) or predicted (3–6) (3:5) type-I bulge turn. (b) Normalized equilibrium unfolding transitions for variants 1 and 7–9 with either a confirmed (7) or predicted (8, 9) (2:2) type-I' -hairpin turn. (c) Normalized equilibrium unfolding transitions for FBP (WW variant 10) with a confirmed (3:5) type-I G1 bulge turn and variant 11 with a predicted (4:6) loop.
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21402934 E.L.Baxter, P.A.Jennings, and J.N.Onuchic (2011).
Interdomain communication revealed in the diabetes drug target mitoNEET.
  Proc Natl Acad Sci U S A, 108, 5266-5271.  
21368203 F.Noé, S.Doose, I.Daidone, M.Löllmann, M.Sauer, J.D.Chodera, and J.C.Smith (2011).
Dynamical fingerprints for probing individual relaxation processes in biomolecular dynamics with simulations and kinetic experiments.
  Proc Natl Acad Sci U S A, 108, 4822-4827.  
21548671 J.H.Prinz, H.Wu, M.Sarich, B.Keller, M.Senne, M.Held, J.D.Chodera, C.Schütte, and F.Noé (2011).
Markov models of molecular kinetics: Generation and validation.
  J Chem Phys, 134, 174105.  
20944750 A.M.Ruschak, T.L.Religa, S.Breuer, S.Witt, and L.E.Kay (2010).
The proteasome antechamber maintains substrates in an unfolded state.
  Nature, 467, 868-871.  
20947758 D.E.Shaw, P.Maragakis, K.Lindorff-Larsen, S.Piana, R.O.Dror, M.P.Eastwood, J.A.Bank, J.M.Jumper, J.K.Salmon, Y.Shan, and W.Wriggers (2010).
Atomic-level characterization of the structural dynamics of proteins.
  Science, 330, 341-346.  
21152000 F.Morcos, S.Chatterjee, C.L.McClendon, P.R.Brenner, R.López-Rendón, J.Zintsmaster, M.Ercsey-Ravasz, C.R.Sweet, M.P.Jacobson, J.W.Peng, and J.A.Izaguirre (2010).
Modeling conformational ensembles of slow functional motions in Pin1-WW.
  PLoS Comput Biol, 6, e1001015.  
20574990 K.Hong Lim, C.K.Hsu, and S.Park (2010).
Flow cytometric analysis of genetic FRET detectors containing variable substrate sequences.
  Biotechnol Prog, 26, 1765-1771.  
21297873 P.L.Freddolino, C.B.Harrison, Y.Liu, and K.Schulten (2010).
Challenges in protein folding simulations: Timescale, representation, and analysis.
  Nat Phys, 6, 751-758.  
19541614 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, and J.W.Kelly (2009).
Evaluating beta-turn mimics as beta-sheet folding nucleators.
  Proc Natl Acad Sci U S A, 106, 11067-11072.
PDB code: 2kbu
19491935 A.I.Bartlett, and S.E.Radford (2009).
An expanding arsenal of experimental methods yields an explosion of insights into protein folding mechanisms.
  Nat Struct Mol Biol, 16, 582-588.  
19887634 F.Noé, C.Schütte, E.Vanden-Eijnden, L.Reich, and T.R.Weikl (2009).
Constructing the equilibrium ensemble of folding pathways from short off-equilibrium simulations.
  Proc Natl Acad Sci U S A, 106, 19011-19016.  
19626709 H.Fu, G.R.Grimsley, A.Razvi, J.M.Scholtz, and C.N.Pace (2009).
Increasing protein stability by improving beta-turns.
  Proteins, 77, 491-498.  
19525973 J.Gao, D.A.Bosco, E.T.Powers, and J.W.Kelly (2009).
Localized thermodynamic coupling between hydrogen bonding and microenvironment polarity substantially stabilizes proteins.
  Nat Struct Mol Biol, 16, 684-690.  
19361525 J.Tang, S.G.Kang, J.G.Saven, and F.Gai (2009).
Characterization of the cofactor-induced folding mechanism of a zinc-binding peptide using computationally designed mutants.
  J Mol Biol, 389, 90.  
19565466 M.Jäger, M.Dendle, and J.W.Kelly (2009).
Sequence determinants of thermodynamic stability in a WW domain--an all-beta-sheet protein.
  Protein Sci, 18, 1806-1813.  
19413983 P.L.Freddolino, S.Park, B.Roux, and K.Schulten (2009).
Force field bias in protein folding simulations.
  Biophys J, 96, 3772-3780.  
19792076 P.Metzner, F.Noé, and C.Schütte (2009).
Estimating the sampling error: distribution of transition matrices and functions of transition matrices for given trajectory data.
  Phys Rev E Stat Nonlin Soft Matter Phys, 80, 021106.  
19399227 R.D.Hills, and C.L.Brooks (2009).
Insights from coarse-grained gō models for protein folding and dynamics.
  Int J Mol Sci, 10, 889-905.  
18275088 A.M.Marcelino, and L.M.Gierasch (2008).
Roles of beta-turns in protein folding: from peptide models to protein engineering.
  Biopolymers, 89, 380-391.  
18601313 F.Noé (2008).
Probability distributions of molecular observables computed from Markov models.
  J Chem Phys, 128, 244103.  
18378442 F.Noé, and S.Fischer (2008).
Transition networks for modeling the kinetics of conformational change in macromolecules.
  Curr Opin Struct Biol, 18, 154-162.  
18844292 M.Jager, S.Deechongkit, E.K.Koepf, H.Nguyen, J.Gao, E.T.Powers, M.Gruebele, and J.W.Kelly (2008).
Understanding the mechanism of beta-sheet folding from a chemical and biological perspective.
  Biopolymers, 90, 751-758.  
18200608 O.Okhrimenko, and I.Jelesarov (2008).
A survey of the year 2006 literature on applications of isothermal titration calorimetry.
  J Mol Recognit, 21, 1.  
18339748 P.L.Freddolino, F.Liu, M.Gruebele, and K.Schulten (2008).
Ten-microsecond molecular dynamics simulation of a fast-folding WW domain.
  Biophys J, 94, L75-L77.  
18676833 Q.Ding, L.Huo, J.Y.Yang, W.Xia, Y.Wei, Y.Liao, C.J.Chang, Y.Yang, C.C.Lai, D.F.Lee, C.J.Yen, Y.J.Chen, J.M.Hsu, H.P.Kuo, C.Y.Lin, F.J.Tsai, L.Y.Li, C.H.Tsai, and M.C.Hung (2008).
Down-regulation of myeloid cell leukemia-1 through inhibiting Erk/Pin 1 pathway by sorafenib facilitates chemosensitization in breast cancer.
  Cancer Res, 68, 6109-6117.  
18708465 R.D.Hills, and C.L.Brooks (2008).
Coevolution of function and the folding landscape: correlation with density of native contacts.
  Biophys J, 95, L57-L59.  
18242977 R.D.Schaeffer, A.Fersht, and V.Daggett (2008).
Combining experiment and simulation in protein folding: closing the gap for small model systems.
  Curr Opin Struct Biol, 18, 4-9.  
17931593 R.V.Pappu, X.Wang, A.Vitalis, and S.L.Crick (2008).
A polymer physics perspective on driving forces and mechanisms for protein aggregation.
  Arch Biochem Biophys, 469, 132-141.  
18650393 S.Gosavi, P.C.Whitford, P.A.Jennings, and J.N.Onuchic (2008).
Extracting function from a beta-trefoil folding motif.
  Proc Natl Acad Sci U S A, 105, 10384-10389.  
17905840 T.R.Weikl (2008).
Transition states in protein folding kinetics: modeling phi-values of small beta-sheet proteins.
  Biophys J, 94, 929-937.  
18554060 Z.Luo, J.Ding, and Y.Zhou (2008).
Folding mechanisms of individual beta-hairpins in a Go model of Pin1 WW domain by all-atom molecular dynamics simulations.
  J Chem Phys, 128, 225103.  
17239580 D.J.Brockwell, and S.E.Radford (2007).
Intermediates: ubiquitous species on folding energy landscapes?
  Curr Opin Struct Biol, 17, 30-37.  
17500733 L.Wu, J.Zhang, J.Wang, W.F.Li, and W.Wang (2007).
Folding behavior of ribosomal protein S6 studied by modified Gō-like model.
  Phys Rev E Stat Nonlin Soft Matter Phys, 75, 031914.  
17586778 M.Jäger, H.Nguyen, M.Dendle, M.Gruebele, and J.W.Kelly (2007).
Influence of hPin1 WW N-terminal domain boundaries on function, protein stability, and folding.
  Protein Sci, 16, 1495-1501.  
17766376 M.Jäger, M.Dendle, A.A.Fuller, and J.W.Kelly (2007).
A cross-strand Trp Trp pair stabilizes the hPin1 WW domain at the expense of function.
  Protein Sci, 16, 2306-2313.  
17334375 T.Peng, J.S.Zintsmaster, A.T.Namanja, and J.W.Peng (2007).
Sequence-specific dynamics modulate recognition specificity in WW domains.
  Nat Struct Mol Biol, 14, 325-331.  
17766370 T.Sharpe, A.L.Jonsson, T.J.Rutherford, V.Daggett, and A.R.Fersht (2007).
The role of the turn in beta-hairpin formation during WW domain folding.
  Protein Sci, 16, 2233-2239.  
16855578 J.W.Kelly (2006).
Structural biology: proteins downhill all the way.
  Nature, 442, 255-256.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.