1MIK

THE ROLE OF WATER MOLECULES IN THE STRUCTURE-BASED DESIGN OF (5-HYDROXYNORVALINE)-2-CYCLOSPORIN: SYNTHESIS, BIOLOGICAL ACTIVITY, AND CRYSTALLOGRAPHIC ANALYSIS WITH CYCLOPHILIN A


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Work: 0.175 
  • R-Value Observed: 0.175 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

The Role of Water Molecules in the Structure-Based Design of (5-Hydroxynorvaline)-2-Cyclosporin: Synthesis, Biological Activity, and Crystallographic Analysis with Cyclophilin A.

Mikol, V.Papageorgiou, C.Borer, X.

(1995) J Med Chem 38: 3361

  • DOI: https://doi.org/10.1021/jm00017a020
  • Primary Citation of Related Structures:  
    1MIK

  • PubMed Abstract: 

    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).


  • Organizational Affiliation

    Sandoz Pharma Ltd., Preclinical Research, Basel, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PEPTIDYL-PROLYL CIS-TRANS ISOMERASE A165Homo sapiensMutation(s): 0 
Gene Names: CYCLOPHILIN
EC: 5.2.1.8
UniProt & NIH Common Fund Data Resources
Find proteins for P62937 (Homo sapiens)
Explore P62937 
Go to UniProtKB:  P62937
PHAROS:  P62937
GTEx:  ENSG00000196262 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP62937
Sequence Annotations
Expand
  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
CYCLOSPORIN A11Tolypocladium inflatumMutation(s): 1 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  5 Unique
IDChains TypeFormula2D DiagramParent
AA4
Query on AA4
B
L-PEPTIDE LINKINGC5 H11 N O3ALA
BMT
Query on BMT
B
L-PEPTIDE LINKINGC10 H19 N O3THR
MLE
Query on MLE
B
L-PEPTIDE LINKINGC7 H15 N O2LEU
MVA
Query on MVA
B
L-PEPTIDE LINKINGC6 H13 N O2VAL
SAR
Query on SAR
B
PEPTIDE LINKINGC3 H7 N O2GLY
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Work: 0.175 
  • R-Value Observed: 0.175 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 36.439α = 90
b = 61.32β = 90
c = 72.575γ = 90
Software Package:
Software NamePurpose
X-PLORmodel building
X-PLORrefinement
X-PLORphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 1996-03-08 
  • Deposition Author(s): Mikol, V.

Revision History  (Full details and data files)

  • Version 1.0: 1996-03-08
    Type: Initial release
  • Version 1.1: 2011-06-14
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2011-07-27
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary
  • Version 1.4: 2012-12-12
    Changes: Other