5DYL

Crystal structure of the cGMP-dependent protein kinase PKG from Plasmodium Vivax - Apo form

Replaces:  4MYI

Summary for 5DYL

• Entry DOI: 10.2210/pdb5dyl/pdb
• Related: 4MYI
• Descriptor: cGMP-dependent protein kinase, putative (2 entities in total)
• Functional Keywords: transferase, kinase, structural genomics, structural genomics consortium, sgc
• Biological source: Plasmodium vivax
• Total number of polymer chains: 1
• Total formula weight: 96726.65

Authors

Wernimont, A.K.,Tempel, W.,He, H.,Seitova, A.,Hills, T.,Neculai, A.M.,Baker, D.A.,Flueck, C.,Kettleborough, C.A.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Hui, R.,Hutchinson, A.,El Bakkouri, M.,Structural Genomics Consortium (SGC) (deposition date: 2015-09-24, release date: 2015-11-04, Last modification date: 2024-03-06)

Primary citation

El Bakkouri, M.,Kouidmi, I.,Wernimont, A.K.,Amani, M.,Hutchinson, A.,Loppnau, P.,Kim, J.J.,Flueck, C.,Walker, J.R.,Seitova, A.,Senisterra, G.,Kakihara, Y.,Kim, C.,Blackman, M.J.,Calmettes, C.,Baker, D.A.,Hui, R.
Structures of the cGMP-dependent protein kinase in malaria parasites reveal a unique structural relay mechanism for activation.
Proc.Natl.Acad.Sci.USA, 116:14164-14173, 2019

PubMed 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 and , 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 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.

PubMed: 31239348
DOI: 10.1073/pnas.1905558116

Experimental method

X-RAY DIFFRACTION (2.4 Å)