5KEZ

Selective and potent inhibition of the glycosidase human amylase by the short and extremely compact peptide piHA from mRNA display


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.83 Å
  • R-Value Free: 0.208 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.179 

wwPDB Validation   3D Report Full Report


This is version 2.0 of the entry. See complete history


Literature

Rapid Discovery of Potent and Selective Glycosidase-Inhibiting De Novo Peptides.

Jongkees, S.A.Caner, S.Tysoe, C.Brayer, G.D.Withers, S.G.Suga, H.

(2017) Cell Chem Biol 24: 381-390

  • DOI: https://doi.org/10.1016/j.chembiol.2017.02.001
  • Primary Citation of Related Structures:  
    5KEZ

  • PubMed Abstract: 

    Human pancreatic α-amylase (HPA) is responsible for degrading starch to malto-oligosaccharides, thence to glucose, and is therefore an attractive therapeutic target for the treatment of diabetes and obesity. Here we report the discovery of a unique lariat nonapeptide, by means of the RaPID (Random non-standard Peptides Integrated Discovery) system, composed of five amino acids in a head-to-side-chain thioether macrocycle and a further four amino acids in a 3 10 helical C terminus. This is a potent inhibitor of HPA (K i  = 7 nM) yet exhibits selectivity for the target over other glycosidases tested. Structural studies show that this nonapeptide forms a compact tertiary structure, and illustrate that a general inhibitory motif involving two phenolic groups is often accessed for tight binding of inhibitors to HPA. Furthermore, the work reported here demonstrates the potential of this methodology for the discovery of de novo peptide inhibitors against other glycosidases.


  • Organizational Affiliation

    Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-0033 Tokyo, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Pancreatic alpha-amylase496Homo sapiensMutation(s): 0 
Gene Names: AMY2A
EC: 3.2.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for P04746 (Homo sapiens)
Explore P04746 
Go to UniProtKB:  P04746
PHAROS:  P04746
GTEx:  ENSG00000243480 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04746
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
ACE-DTY-PRO-TYR-SER-CYS-TRP-VAL-ARG-HIS-NH211synthetic constructMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PCA
Query on PCA
A
L-PEPTIDE LINKINGC5 H7 N O3GLN
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.83 Å
  • R-Value Free: 0.208 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.179 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 52.8α = 90
b = 75.84β = 90
c = 137.26γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Canadian Glycomics Network/ Networks of Centres of ExcellenceCanada--

Revision History  (Full details and data files)

  • Version 1.0: 2017-03-29
    Type: Initial release
  • Version 2.0: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Polymer sequence, Refinement description