Crystal structures of the carboxyl cGMP binding domain of plasmodium falciparumcGMP-dependent protein kinase reveals a novel salt bridge crucial for activation

Jeong Joo Kim,Eduardo Sanabria Figueroa,Choel Kim,Eugen Franz,Daniela Bertinetti,Friedrich Herberg

doi:10.1186/2050-6511-14-s1-p33

Abstract

Background Plasmodium falciparum cGMP-dependent protein kinase (pfPKG) is a validated therapeutic target of malaria. As a key regulator of its life cycle, pfPKG plays a crucial role in both the sexual and asexual blood-stages that cause malaria pathology. Inhibiting pfPKG blocks proliferation and transmission of the parasite [1,2]. However the development of pfPKG-specific inhibitor has been greatly hampered by the lack of high-resolution structure information to guide drug design. Targeting the ATP binding site of pfPKG is an approach commonly associated with low specificity and toxicity [3]. Therefore, we aim to target a domain that is unique to this kinase, the cyclic nucleotide binding (CNB) domain. Since previous studies demonstrated the fourth-cyclic nucleotide binding (CNB-D) domain of pfPKG to be the most important for the kinase activation [4] we focused on this domain to understand its role in cGMP dependent activation.

Highlights

Plasmodium falciparum cGMP-dependent protein kinase is a validated therapeutic target of malaria
Since previous studies demonstrated the fourth-cyclic nucleotide binding (CNB-D) domain of pfPKG to be the most important for the kinase activation [4] we focused on this domain to understand its role in cGMP dependent activation
The structure of the cGMP complex reveals that CNB-D binds cGMP through [1] leucine and arginine residues on the b5 strand and a threonine within the phosphate binding cassette (PBC) that interact with the guanine moiety through hydrogen bonding

Summary

Introduction

Plasmodium falciparum cGMP-dependent protein kinase (pfPKG) is a validated therapeutic target of malaria. As a key regulator of its life cycle, pfPKG plays a crucial role in both the sexual and asexual blood-stages that cause malaria pathology. The development of pfPKG-specific inhibitor has been greatly hampered by the lack of high-resolution structure information to guide drug design. Targeting the ATP binding site of pfPKG is an approach commonly associated with low specificity and toxicity [3]. We aim to target a domain that is unique to this kinase, the cyclic nucleotide binding (CNB) domain. Since previous studies demonstrated the fourth-cyclic nucleotide binding (CNB-D) domain of pfPKG to be the most important for the kinase activation [4] we focused on this domain to understand its role in cGMP dependent activation

Objectives

Results

Conclusion