PDBsum entry 5e16

Transferase

PDB id: 5e16

Contents

Protein chain

138 a.a.

Ligands

PCG

Waters ×104

PDB id:

5e16

Name:

Transferase

Title:

Co-crystal structure of the n-termial cgmp binding domain of plasmodium falciparum pkg with cgmp

Structure:

Cgmp-dependent protein kinase. Chain: a. Fragment: cgmp binding domain (unp residues 21-162). Engineered: yes

Source:

Plasmodium falciparum. Organism_taxid: 5833. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.65Å R-factor: 0.197 R-free: 0.227

Authors:

M.El Bakkouri,J.R.Walker,P.Loppnau,C.H.Arrowsmith,A.M.Edwards, C.Bountra,R.Hui,Structural Genomics Consortium (Sgc)

Key ref:

M.El Bakkouri et al. (2019). Structures of the cGMP-dependent protein kinase in malaria parasites reveal a unique structural relay mechanism for activation. Proc Natl Acad Sci U S A, 116, 14164-14173. PubMed id: 31239348 DOI: 10.1073/pnas.1905558116

Date:

29-Sep-15 Release date: 04-Nov-15

Protein chain

Q8I719  (Q8I719_PLAF7) -  cGMP-dependent protein kinase from Plasmodium falciparum (isolate 3D7)

Seq: 853 a.a.

Struc: 138 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.12 - cGMP-dependent protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] (Bound ligand (Het Group name = PCG) matches with 78.57% similarity) + ADP + H(+)

L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] (Bound ligand (Het Group name = PCG) matches with 78.57% similarity) + ADP + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1073/pnas.1905558116

Proc Natl Acad Sci U S A 116:14164-14173 (2019)

PubMed id: 31239348

Structures of the cGMP-dependent protein kinase in malaria parasites reveal a unique structural relay mechanism for activation.

M.El Bakkouri, I.Kouidmi, A.K.Wernimont, M.Amani, A.Hutchinson, P.Loppnau, J.J.Kim, C.Flueck, J.R.Walker, A.Seitova, G.Senisterra, Y.Kakihara, C.Kim, M.J.Blackman, C.Calmettes, D.A.Baker, R.Hui.

ABSTRACT

The cyclic guanosine-3',5'-monophosphate (cGMP)-dependent protein kinase (PKG) was identified >25 y ago; however, efforts to obtain a structure of the entire PKG enzyme or catalytic domain from any species have failed. In malaria parasites, cooperative activation of PKG triggers crucial developmental transitions throughout the complex life cycle. We have determined the cGMP-free crystallographic structures of PKG from Plasmodium falciparum and Plasmodium vivax, revealing how key structural components, including an N-terminal autoinhibitory segment (AIS), four predicted cyclic nucleotide-binding domains (CNBs), and a kinase domain (KD), are arranged when the enzyme is inactive. The four CNBs and the KD are in a pentagonal configuration, with the AIS docked in the substrate site of the KD in a swapped-domain dimeric arrangement. We show that although the protein is predominantly a monomer (the dimer is unlikely to be representative of the physiological form), the binding of the AIS is necessary to keep Plasmodium PKG inactive. A major feature is a helix serving the dual role of the N-terminal helix of the KD as well as the capping helix of the neighboring CNB. A network of connecting helices between neighboring CNBs contributes to maintaining the kinase in its inactive conformation. We propose a scheme in which cooperative binding of cGMP, beginning at the CNB closest to the KD, transmits conformational changes around the pentagonal molecule in a structural relay mechanism, enabling PKG to orchestrate rapid, highly regulated developmental switches in response to dynamic modulation of cGMP levels in the parasite.