6HWO

Crystal structure of human phosphodiesterase 4D2 catalytic domain with inhibitor NPD-1335


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.201 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors (Part 2).

de Heuvel, E.Singh, A.K.Boronat, P.Kooistra, A.J.van der Meer, T.Sadek, P.Blaazer, A.R.Shaner, N.C.Bindels, D.S.Caljon, G.Maes, L.Sterk, G.J.Siderius, M.Oberholzer, M.de Esch, I.J.P.Brown, D.G.Leurs, R.

(2019) Bioorg Med Chem 27: 4013-4029

  • DOI: https://doi.org/10.1016/j.bmc.2019.06.026
  • Primary Citation of Related Structures:  
    6GXQ, 6HWO, 6RB6, 6RCW, 6RFN, 6RFW, 6RGK

  • PubMed Abstract: 

    Inhibitors against Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) and B2 (TbrPDEB2) have gained interest as new treatments for human African trypanosomiasis. The recently reported alkynamide tetrahydrophthalazinones, which show submicromolar activities against TbrPDEB1 and anti-T. brucei activity, have been used as starting point for the discovery of new TbrPDEB1 inhibitors. Structure-based design indicated that the alkynamide-nitrogen atom can be readily decorated, leading to the discovery of 37, a potent TbrPDEB1 inhibitor with submicromolar activities against T. brucei parasites. Furthermore, 37 is more potent against TbrPDEB1 than hPDE4 and shows no cytotoxicity on human MRC-5 cells. The crystal structures of the catalytic domain of TbrPDEB1 co-crystalized with several different alkynamides show a bidentate interaction with key-residue Gln874, but no interaction with the parasite-specific P-pocket, despite being (uniquely) a more potent inhibitor for the parasite PDE. Incubation of blood stream form trypanosomes by 37 increases intracellular cAMP levels and results in the distortion of the cell cycle and cell death, validating phosphodiesterase inhibition as mode of action.


  • 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
cAMP-specific 3',5'-cyclic phosphodiesterase 4D
A, B, C, D
364Homo sapiensMutation(s): 0 
Gene Names: PDE4DDPDE3
EC: 3.1.4.53
UniProt & NIH Common Fund Data Resources
Find proteins for Q08499 (Homo sapiens)
Explore Q08499 
Go to UniProtKB:  Q08499
PHAROS:  Q08499
GTEx:  ENSG00000113448 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ08499
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 7 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FFZ (Subject of Investigation/LOI)
Query on FFZ

Download Ideal Coordinates CCD File 
KA [auth B],
Q [auth A],
RB [auth D],
YA [auth C]
3-[5-[(4aR,8aS)-4-OXIDANYLIDENE-3-PROPAN-2-YL-4a,5,8,8a-TETRAHYDROPHTHALAZIN-1-YL]-2-METHOXY-PHENYL]-N-(PHENYLMETHYL)PROP-2-YNAMIDE
C28 H29 N3 O3
CNKULZYKNGMIIR-BJKOFHAPSA-N
EPE
Query on EPE

Download Ideal Coordinates CCD File 
OA [auth B],
RA [auth C],
X [auth A],
ZB [auth D]
4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID
C8 H18 N2 O4 S
JKMHFZQWWAIEOD-UHFFFAOYSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
AC [auth D],
JA [auth B],
M [auth A],
Y [auth A],
ZA [auth C]
DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
EB [auth D],
IA [auth B],
JB [auth D]
DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
GA [auth B],
N [auth A],
OB [auth D],
XA [auth C]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
AA [auth B]
BA [auth B]
BB [auth C]
CA [auth B]
CB [auth C]
AA [auth B],
BA [auth B],
BB [auth C],
CA [auth B],
CB [auth C],
DA [auth B],
DB [auth D],
E [auth A],
EA [auth B],
F [auth A],
FA [auth B],
FB [auth D],
G [auth A],
GB [auth D],
H [auth A],
HA [auth B],
HB [auth D],
I [auth A],
IB [auth D],
J [auth A],
K [auth A],
KB [auth D],
L [auth A],
LB [auth D],
MA [auth B],
MB [auth D],
NA [auth B],
NB [auth D],
O [auth A],
P [auth A],
PA [auth C],
PB [auth D],
QA [auth C],
QB [auth D],
S [auth A],
SA [auth C],
T [auth A],
TA [auth C],
TB [auth D],
U [auth A],
UA [auth C],
UB [auth D],
V [auth A],
VA [auth C],
VB [auth D],
W [auth A],
WA [auth C],
WB [auth D],
XB [auth D],
YB [auth D],
Z [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
AB [auth C],
LA [auth B],
R [auth A],
SB [auth D]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
FFZ BindingDB:  6HWO Ki: 794 (nM) from 1 assay(s)
Kd: 79 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.201 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 98.465α = 90
b = 110.848β = 90
c = 160.461γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
DIALSdata reduction
Aimlessdata scaling
Cootmodel building

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
European Union602666

Revision History  (Full details and data files)

  • Version 1.0: 2019-07-24
    Type: Initial release
  • Version 1.1: 2019-08-14
    Changes: Data collection, Database references
  • Version 1.2: 2019-09-04
    Changes: Data collection, Database references
  • Version 1.3: 2024-01-24
    Changes: Data collection, Database references, Derived calculations, Refinement description