PDBsum entry 1mik

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protein Protein-protein interface(s) links
Isomerase/immunosuppressant PDB id
Protein chains
165 a.a. *
11 a.a. *
Waters ×188
* Residue conservation analysis
PDB id:
Name: Isomerase/immunosuppressant
Title: The role of water molecules in the structure-based design of hydroxynorvaline)-2-cyclosporin: synthesis, biological acti crystallographic analysis with cyclophilin a
Structure: Peptidyl-prolyl cis-trans isomerase a. Chain: a. Synonym: ppiase, rotamase, cyclophilin a. Engineered: yes. Cyclosporin a. Chain: b. Synonym: cyclosporine, ciclosporin, ciclosporine. Engineered: yes. Mutation: yes.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: cyclophilin. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Tolypocladium inflatum. Organism_taxid: 29910
1.76Å     R-factor:   0.175    
Authors: V.Mikol
Key ref: V.Mikol et al. (1995). The role of water molecules in the structure-based design of (5-hydroxynorvaline)-2-cyclosporin: synthesis, biological activity, and crystallographic analysis with cyclophilin A. J Med Chem, 38, 3361-3367. PubMed id: 7650689 DOI: 10.1021/jm00017a020
20-Sep-95     Release date:   08-Mar-96    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P62937  (PPIA_HUMAN) -  Peptidyl-prolyl cis-trans isomerase A
165 a.a.
165 a.a.
Protein chain
No UniProt id for this chain
Struc: 11 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chain A: 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     extracellular region   8 terms 
  Biological process     viral reproduction   18 terms 
  Biochemical function     protein binding     7 terms  


    Added reference    
DOI no: 10.1021/jm00017a020 J Med Chem 38:3361-3367 (1995)
PubMed id: 7650689  
The role of water molecules in the structure-based design of (5-hydroxynorvaline)-2-cyclosporin: synthesis, biological activity, and crystallographic analysis with cyclophilin A.
V.Mikol, C.Papageorgiou, X.Borer.
Analysis of the contact surface of the cyclophilin A (CypA)/cyclosporin A (CsA, 1) crystal structure delineates a unique cavity between both molecules in the vicinity of the Abu-2 side chain atoms of 1 (Abu pocket). Therefore, (5-hydroxynorvaline)-2-cyclosporin (2) was designed and prepared as a CsA derivative which could mediate additional interactions within the pocket. The X-ray crystal structure of the CypA/2 complex at 1.76 A resolution shows that 1 and 2 have identical backbone conformations and that the introduced hydroxypropyl chain makes indeed the expected supplemental interactions with CypA. However, 2 has 8-9-fold lower binding affinity than 1 for CypA. This results from a presumed unfavorable free energy change associated with the displacement of one of the tightly bound water molecules within the pocket and a change in prebinding equilibria. The role of the later was assessed by comparing the conformation distribution of 1 and 2 to that of norvaline-2-cyclosporin (3) and norvaline-2-(D-MeSer)-3-cyclosporin (4).

Literature references that cite this PDB file's key reference

  PubMed id Reference
19461869 S.Wong, R.E.Amaro, and J.A.McCammon (2009).
MM-PBSA Captures Key Role of Intercalating Water Molecules at a Protein-Protein Interface.
  J Chem Theory Comput, 5, 422-429.  
17551641 J.Cluzeau, S.Oishi, H.Ohno, Z.Wang, B.Evans, S.C.Peiper, and N.Fujii (2007).
Design and synthesis of all diastereomers of cyclic pseudo-dipeptides as mimics of cyclic CXCR4 pentapeptide antagonists.
  Org Biomol Chem, 5, 1915-1923.  
17425297 J.Seo, J.Igarashi, H.Li, P.Martasek, L.J.Roman, T.L.Poulos, and R.B.Silverman (2007).
Structure-based design and synthesis of N(omega)-nitro-L-arginine-containing peptidomimetics as selective inhibitors of neuronal nitric oxide synthase. Displacement of the heme structural water.
  J Med Chem, 50, 2089-2099.
PDB codes: 2hx2 2hx3 2hx4
17242738 Z.Li, and T.Lazaridis (2007).
Water at biomolecular binding interfaces.
  Phys Chem Chem Phys, 9, 573-581.  
16374623 A.T.García-Sosa, and R.L.Mancera (2006).
The effect of a tightly bound water molecule on scaffold diversity in the computer-aided de novo ligand design of CDK2 inhibitors.
  J Mol Model, 12, 422-431.  
15333922 A.K.Pedersen, G.H.Peters G, K.B.Møller, L.F.Iversen, and J.S.Kastrup (2004).
Water-molecule network and active-site flexibility of apo protein tyrosine phosphatase 1B.
  Acta Crystallogr D Biol Crystallogr, 60, 1527-1534.
PDB code: 1sug
12756610 A.T.García-Sosa, R.L.Mancera, and P.M.Dean (2003).
WaterScore: a novel method for distinguishing between bound and displaceable water molecules in the crystal structure of the binding site of protein-ligand complexes.
  J Mol Model, 9, 172-182.  
11058892 M.T.Ivery (2000).
Immunophilins: switched on protein binding domains?
  Med Res Rev, 20, 452-484.  
9753693 E.Chung, D.Henriques, D.Renzoni, M.Zvelebil, J.M.Bradshaw, G.Waksman, C.V.Robinson, and J.E.Ladbury (1998).
Mass spectrometric and thermodynamic studies reveal the role of water molecules in complexes formed between SH2 domains and tyrosyl phosphopeptides.
  Structure, 6, 1141-1151.  
  9792092 P.C.Sanschagrin, and L.A.Kuhn (1998).
Cluster analysis of consensus water sites in thrombin and trypsin shows conservation between serine proteases and contributions to ligand specificity.
  Protein Sci, 7, 2054-2064.  
8768903 H.J.Böhm (1996).
Current computational tools for de novo ligand design.
  Curr Opin Biotechnol, 7, 433-436.  
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