5G2B

Crystal structure of T. brucei PDE-B1 catalytic domain with inhibitor NPD-008


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.83 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.185 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity.

Blaazer, A.R.Singh, A.K.de Heuvel, E.Edink, E.Orrling, K.M.Veerman, J.J.N.van den Bergh, T.Jansen, C.Balasubramaniam, E.Mooij, W.J.Custers, H.Sijm, M.Tagoe, D.N.A.Kalejaiye, T.D.Munday, J.C.Tenor, H.Matheeussen, A.Wijtmans, M.Siderius, M.de Graaf, C.Maes, L.de Koning, H.P.Bailey, D.S.Sterk, G.J.de Esch, I.J.P.Brown, D.G.Leurs, R.

(2018) J Med Chem 61: 3870-3888

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b01670
  • Primary Citation of Related Structures:  
    5G2B, 5G57, 5G5V, 5L8C, 5L8Y, 5L9H, 5LAQ, 5LBO

  • PubMed Abstract: 

    Several trypanosomatid cyclic nucleotide phosphodiesterases (PDEs) possess a unique, parasite-specific cavity near the ligand-binding region that is referred to as the P-pocket. One of these enzymes, Trypanosoma brucei PDE B1 (TbrPDEB1), is considered a drug target for the treatment of African sleeping sickness. Here, we elucidate the molecular determinants of inhibitor binding and reveal that the P-pocket is amenable to directed design. By iterative cycles of design, synthesis, and pharmacological evaluation and by elucidating the structures of inhibitor-bound TbrPDEB1, hPDE4B, and hPDE4D complexes, we have developed 4a,5,8,8a-tetrahydrophthalazinones as the first selective TbrPDEB1 inhibitor series. Two of these, 8 (NPD-008) and 9 (NPD-039), were potent ( K i = 100 nM) TbrPDEB1 inhibitors with antitrypanosomal effects (IC 50 = 5.5 and 6.7 μM, respectively). Treatment of parasites with 8 caused an increase in intracellular cyclic adenosine monophosphate (cAMP) levels and severe disruption of T. brucei cellular organization, chemically validating trypanosomal PDEs as therapeutic targets in trypanosomiasis.


  • Organizational Affiliation

    Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems , Vrije Universiteit Amsterdam , 1081 HZ Amsterdam , The Netherlands.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CLASS 1 PHOSPHODIESTERASE PDEB1
A, B
360Trypanosoma bruceiMutation(s): 0 
EC: 3.1.4
UniProt
Find proteins for Q8WQX9 (Trypanosoma brucei)
Explore Q8WQX9 
Go to UniProtKB:  Q8WQX9
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8WQX9
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
LQY
Query on LQY

Download Ideal Coordinates CCD File 
E [auth A],
M [auth B]
N-(2-amino-2-oxoethyl)-5'-[(4aR,8aS)-3-cycloheptyl-4-oxo-3,4,4a,5,8,8a-hexahydrophthalazin-1-yl]-2'-methoxy[1,1'-biphenyl]-4-carboxamide
C31 H36 N4 O4
VZKJWTFPORBEEH-LOSJGSFVSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
O [auth B]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
C [auth A],
K [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
GAI
Query on GAI

Download Ideal Coordinates CCD File 
I [auth A],
J [auth A],
N [auth B]
GUANIDINE
C H5 N3
ZRALSGWEFCBTJO-UHFFFAOYSA-N
FMT
Query on FMT

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A],
H [auth A]
FORMIC ACID
C H2 O2
BDAGIHXWWSANSR-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
D [auth A],
L [auth B]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
LQY BindingDB:  5G2B Ki: min: 39.8, max: 100 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.83 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.185 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 114.36α = 90
b = 115.74β = 108.7
c = 68.41γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-11-29
    Type: Initial release
  • Version 1.1: 2018-05-02
    Changes: Data collection, Database references
  • Version 1.2: 2018-07-11
    Changes: Data collection, Database references
  • Version 1.3: 2019-01-30
    Changes: Data collection, Experimental preparation
  • Version 1.4: 2019-04-03
    Changes: Data collection, Experimental preparation
  • Version 1.5: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description