RCSB PDB - 1TBF: Catalytic Domain Of Human Phosphodiesterase 5A in Complex with Sildenafil

 1TBF

Catalytic Domain Of Human Phosphodiesterase 5A in Complex with Sildenafil


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 Å
  • R-Value Free: 0.185 
  • R-Value Work: 0.157 
  • R-Value Observed: 0.159 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

A Glutamine Switch Mechanism for Nucleotide Selectivity by Phosphodiesterases

Zhang, K.Y.J.Card, G.L.Suzuki, Y.Artis, D.R.Fong, D.Gillette, S.Hsieh, D.Neiman, J.West, B.L.Zhang, C.Milburn, M.V.Kim, S.-H.Schlessinger, J.Bollag, G.

(2004) Mol Cell 15: 279-286

  • DOI: https://doi.org/10.1016/j.molcel.2004.07.005
  • Primary Citation of Related Structures:  
    1T9R, 1T9S, 1TAZ, 1TB5, 1TB7, 1TBB, 1TBF

  • PubMed Abstract: 

    Phosphodiesterases (PDEs) comprise a family of enzymes that modulate the immune response, inflammation, and memory, among many other functions. There are three types of PDEs: cAMP-specific, cGMP-specific, and dual-specific. Here we describe the mechanism of nucleotide selectivity on the basis of high-resolution co-crystal structures of the cAMP-specific PDE4B and PDE4D with AMP, the cGMP-specific PDE5A with GMP, and the apo-structure of the dual-specific PDE1B. These structures show that an invariant glutamine functions as the key specificity determinant by a "glutamine switch" mechanism for recognizing the purine moiety in cAMP or cGMP. The surrounding residues anchor the glutamine residue in different orientations for cAMP and for cGMP. The PDE1B structure shows that in dual-specific PDEs a key histidine residue may enable the invariant glutamine to toggle between cAMP and cGMP. The structural understanding of nucleotide binding enables the design of new PDE inhibitors that may treat diseases in which cyclic nucleotides play a critical role.


  • Organizational Affiliation

    Plexxikon Inc., 91 Bolivar Drive, Berkeley, CA 94710, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
cGMP-specific 3',5'-cyclic phosphodiesterase347Homo sapiensMutation(s): 18 
Gene Names: PDE5APDE5
EC: 3.1.4.17 (PDB Primary Data), 3.1.4.35 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for O76074 (Homo sapiens)
Explore O76074 
Go to UniProtKB:  O76074
PHAROS:  O76074
GTEx:  ENSG00000138735 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO76074
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
VIA BindingDB:  1TBF Ki: min: 1.6, max: 25 (nM) from 5 assay(s)
IC50: min: 0.3, max: 1000 (nM) from 35 assay(s)
EC50: min: 8.7, max: 1000 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 Å
  • R-Value Free: 0.185 
  • R-Value Work: 0.157 
  • R-Value Observed: 0.159 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 76.097α = 90
b = 76.097β = 90
c = 99.272γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
Blu-Icedata collection
ELVESdata scaling
EPMRphasing

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2004-08-03
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.3: 2021-10-27
    Changes: Database references, Derived calculations, Structure summary
  • Version 1.4: 2023-08-23
    Changes: Data collection, Refinement description