4OFG

Co-crystal structure of carboxy cGMP binding domain of Plasmodium falciparum PKG with cGMP


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Crystal Structures of the Carboxyl cGMP Binding Domain of the Plasmodium falciparum cGMP-dependent Protein Kinase Reveal a Novel Capping Triad Crucial for Merozoite Egress.

Kim, J.J.Flueck, C.Franz, E.Sanabria-Figueroa, E.Thompson, E.Lorenz, R.Bertinetti, D.Baker, D.A.Herberg, F.W.Kim, C.

(2015) PLoS Pathog 11: e1004639-e1004639

  • DOI: https://doi.org/10.1371/journal.ppat.1004639
  • Primary Citation of Related Structures:  
    4OFF, 4OFG

  • PubMed Abstract: 

    The Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) is a key regulator across the malaria parasite life cycle. Little is known about PfPKG's activation mechanism. Here we report that the carboxyl cyclic nucleotide binding domain functions as a "gatekeeper" for activation by providing the highest cGMP affinity and selectivity. To understand the mechanism, we have solved its crystal structures with and without cGMP at 2.0 and 1.9 Å, respectively. These structures revealed a PfPKG-specific capping triad that forms upon cGMP binding, and disrupting the triad reduces kinase activity by 90%. Furthermore, mutating these residues in the parasite prevents blood stage merozoite egress, confirming the essential nature of the triad in the parasite. We propose a mechanism of activation where cGMP binding allosterically triggers the conformational change at the αC-helix, which bridges the regulatory and catalytic domains, causing the capping triad to form and stabilize the active conformation.


  • Organizational Affiliation

    Department of Pharmacology, Baylor College of Medicine, Houston, Texas, United States of America; Department of Biochemistry, University of Kassel, Kassel, Hesse, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CGMP-dependent protein kinase144Plasmodium falciparumMutation(s): 0 
EC: 2.7.11.12
UniProt
Find proteins for Q8I719 (Plasmodium falciparum (isolate 3D7))
Explore Q8I719 
Go to UniProtKB:  Q8I719
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8I719
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
PCG
Query on PCG

Download Ideal Coordinates CCD File 
B [auth A]CYCLIC GUANOSINE MONOPHOSPHATE
C10 H12 N5 O7 P
ZOOGRGPOEVQQDX-UUOKFMHZSA-N
N2P
Query on N2P

Download Ideal Coordinates CCD File 
C [auth A]
D [auth A]
E [auth A]
F [auth A]
G [auth A]
C [auth A],
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A]
PENTANE-1,5-DIAMINE
C5 H14 N2
VHRGRCVQAFMJIZ-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
I [auth A],
J [auth A],
K [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
EOH
Query on EOH

Download Ideal Coordinates CCD File 
L [auth A]
M [auth A]
N [auth A]
O [auth A]
P [auth A]
L [auth A],
M [auth A],
N [auth A],
O [auth A],
P [auth A],
Q [auth A],
R [auth A],
S [auth A],
T [auth A],
U [auth A],
V [auth A],
W [auth A],
X [auth A]
ETHANOL
C2 H6 O
LFQSCWFLJHTTHZ-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 67.299α = 90
b = 67.299β = 90
c = 59.518γ = 120
Software Package:
Software NamePurpose
Specdata collection
PHASESphasing
PHENIXrefinement
MOSFLMdata reduction
SCALAdata 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: 2015-01-21
    Type: Initial release
  • Version 1.1: 2015-02-11
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations