2ER7

X-RAY ANALYSES OF ASPARTIC PROTEINASES.III. THREE-DIMENSIONAL STRUCTURE OF ENDOTHIAPEPSIN COMPLEXED WITH A TRANSITION-STATE ISOSTERE INHIBITOR OF RENIN AT 1.6 ANGSTROMS RESOLUTION


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Work: 0.142 

wwPDB Validation   3D Report Full Report


This is version 2.0 of the entry. See complete history


Literature

X-ray analyses of aspartic proteinases. III Three-dimensional structure of endothiapepsin complexed with a transition-state isostere inhibitor of renin at 1.6 A resolution.

Veerapandian, B.Cooper, J.B.Sali, A.Blundell, T.L.

(1990) J Mol Biol 216: 1017-1029

  • DOI: https://doi.org/10.1016/S0022-2836(99)80017-5
  • Primary Citation of Related Structures:  
    2ER7

  • PubMed Abstract: 

    The aspartic proteinase, endothiapepsin (EC 3.4.23.6), was complexed with a highly potent renin inhibitor, H-261 (t-Boc-His-Pro-Phe-His-LeuOHVal-Ile-His), where OH denotes a hydroxyethylene (-(S) CHOH-CH2-) transition-state isostere in the scissile bond surrogate. Crystals were grown in a form that has the same space group P2(1) as the uncomplexed enzyme, but with a 10 A decrease in the length of the alpha-axis and a 13 degrees decrease in the beta-angle. X-ray data have been collected to a resolution of 1.6 A. The rotation and translation parameters defining the position of the enzyme in the unit cell were determined previously using another enzyme-inhibitor complex that crystallized isomorphously with that of H-261. The molecule was refined using restrained least-squares refinement and the positions of non-hydrogen atoms of the inhibitor and water molecules were defined by difference Fourier techniques. The enzyme-inhibitor complex and 322 water molecules were further refined to a crystallographic R-factor of 0.14. Apart from a small rigid group rotation of a domain comprising residues 190 to 302 and small movements in the flap, there is little difference in conformation between the complexed and uncomplexed forms of the enzyme. The inhibitor is bound in an extended conformation along the active site cleft, and the hydroxyl group of the hydroxyethylene moiety is hydrogen-bonded to both catalytic aspartate carboxylates. The complex is stabilized by hydrogen bonds between the main-chain of the inhibitor and the enzyme. All side-chains of the inhibitor are in van der Waals' contact with groups in the enzyme and define a series of specificity pockets along the active site cleft. The study provides useful clues as to how this potent renin inhibitor (IC50 value of 0.7 x 10(-9) M) may bind renin. In particular it defines the interactions of the hydroxyethylene transition-state isostere with the enzyme more precisely than has been previously possible and therefore provides a useful insight into interactions in the transition state complex.


  • Organizational Affiliation

    Department of Crystallography, Birkbeck College, London, U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ENDOTHIAPEPSINA [auth E]330Cryphonectria parasiticaMutation(s): 0 
EC: 3.4.23.6
UniProt
Find proteins for P11838 (Cryphonectria parasitica)
Explore P11838 
Go to UniProtKB:  P11838
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP11838
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
TRANSITION-STATE ISOSTERE INHIBITOR OF RENINB [auth I]8N/AMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Small Molecules
Biologically Interesting Molecules (External Reference) 1 Unique
Entity ID: 2
IDChains NameType/Class2D Diagram3D Interactions
PRD_000267
Query on PRD_000267
B [auth I]H-261 OligopeptidePeptide-like / Inhibitor
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Work: 0.142 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43α = 90
b = 75.7β = 97
c = 42.9γ = 90
Software Package:
Software NamePurpose
PROLSQrefinement

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 1991-01-15
    Type: Initial release
  • Version 1.1: 2008-03-03
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary, Version format compliance
  • Version 1.3: 2012-12-12
    Changes: Other
  • Version 1.4: 2017-11-29
    Changes: Derived calculations, Other
  • Version 2.0: 2023-11-15
    Changes: Atomic model, Data collection, Database references, Derived calculations