1FQ5

X-ray structure of a cyclic statine inhibitor PD-129,541 bound to yeast proteinase A


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.280 
  • R-Value Observed: 0.200 

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Ligand Structure Quality Assessment 


This is version 2.0 of the entry. See complete history


Literature

X-ray structures of five renin inhibitors bound to saccharopepsin: exploration of active-site specificity.

Cronin, N.B.Badasso, M.O.J Tickle, I.Dreyer, T.Hoover, D.J.Rosati, R.L.Humblet, C.C.Lunney, E.A.Cooper, J.B.

(2000) J Mol Biol 303: 745-760

  • DOI: https://doi.org/10.1006/jmbi.2000.4181
  • Primary Citation of Related Structures:  
    1FQ4, 1FQ5, 1FQ6, 1FQ7, 1FQ8

  • PubMed Abstract: 

    Saccharopepsin is a vacuolar aspartic proteinase involved in activation of a number of hydrolases. The enzyme has great structural homology to mammalian aspartic proteinases including human renin and we have used it as a model system to study the binding of renin inhibitors by X-ray crystallography. Five medium-to-high resolution structures of saccharopepsin complexed with transition-state analogue renin inhibitors were determined. The structure of a cyclic peptide inhibitor (PD-129,541) complexed with the proteinase was solved to 2.5 A resolution. This inhibitor has low affinity for human renin yet binds very tightly to the yeast proteinase (K(i)=4 nM). The high affinity of this inhibitor can be attributed to its bulky cyclic moiety spanning P(2)-P(3)' and other residues that appear to optimally fit the binding sub-sites of the enzyme. Superposition of the saccharopepsin structure on that of renin showed that a movement of the loop 286-301 relative to renin facilitates tighter binding of this inhibitor to saccharopepsin. Our 2.8 A resolution structure of the complex with CP-108,420 shows that its benzimidazole P(3 )replacement retains one of the standard hydrogen bonds that normally involve the inhibitor's main-chain. This suggests a non-peptide lead in overcoming the problem of susceptible peptide bonds in the design of aspartic proteinase inhibitors. CP-72,647 which possesses a basic histidine residue at P(2), has a high affinity for renin (K(i)=5 nM) but proves to be a poor inhibitor for saccharopepsin (K(i)=3.7 microM). This may stem from the fact that the histidine residue would not bind favourably with the predominantly hydrophobic S(2) sub-site of saccharopepsin.


  • Organizational Affiliation

    Department of Crystallography, Birkbeck College, University of London, London, WC1E 7HX, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
SACCHAROPEPSIN329Saccharomyces cerevisiaeMutation(s): 0 
EC: 3.4.23.25
Membrane Entity: Yes 
UniProt
Find proteins for P07267 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P07267 
Go to UniProtKB:  P07267
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP07267
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
beta-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
B
5N-Glycosylation
Glycosylation Resources
GlyTouCan:  G28438DM
GlyCosmos:  G28438DM
GlyGen:  G28438DM
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0GM
Query on 0GM

Download Ideal Coordinates CCD File 
D [auth A]N-[(5S,9S,10S,13S)-9-hydroxy-5,10-bis(2-methylpropyl)-4,7,12,16-tetraoxo-3,6,11,17-tetraazabicyclo[17.3.1]tricosa-1(23),19,21-trien-13-yl]-3-(naphthalen-1-yl)-2-(naphthalen-1-ylmethyl)propanamide
C51 H61 N5 O6
KFCMUWOMPCWWCH-AXYJRABVSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
C [auth A]2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0GM Binding MOAD:  1FQ5 Ki: 4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.280 
  • R-Value Observed: 0.200 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 87.3α = 90
b = 87.3β = 90
c = 110.7γ = 120
Software Package:
Software NamePurpose
MOSFLMdata reduction
ROTAVATAdata reduction
AMoREphasing
RESTRAINrefinement
CCP4data scaling
ROTAVATAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2000-09-20
    Type: Initial release
  • Version 1.1: 2008-04-01
    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: 2016-12-14
    Changes: Structure summary
  • Version 1.4: 2017-10-04
    Changes: Refinement description
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Database references, Derived calculations, Non-polymer description, Structure summary