title: The crystal structure of the MAP kinase LmaMPK10 from Leishmania major reveals parasite-specific features and regulatory mechanisms.
abstract: Mitogen-activated protein kinases (MAPKs) are involved in environmental signal sensing. They are thus expected to play key roles in the biology of Trypanosomatid parasites, which display complex life cycles and use extracellular cues to modulate cell differentiation. Despite their relevance, structural data of Trypanosomatid MAPKs is lacking. We have now determined the crystal structure of Leishmania major LmaMPK10, a stage-specifically activated MAPK, both alone and in complex with SB203580. LmaMPK10 was observed to be more similar to p38 than to other human MAPKs. However, significant differences could be identified in the catalytic pocket, as well as in potentially regulatory sites in the N-terminal lobe. The modified pocket architecture in LmaMPK10 precludes DFG-in/DFG-out regulatory flipping as observed in mammalian MAPKs. LmaMPK10-nucleotide association was also studied, revealing a potential C-terminal autoinhibitory mechanism. Overall, these data should speed the discovery of molecules interfering with LmaMPK10 functions, with relevance for antileishmanial drug development strategies.
authors.affiliation: Unit of Protein Crystallography, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay.
authors.forename: Sofía
authors.initials: S
authors.lastname: Horjales
authors.forename: Dirk
authors.initials: D
authors.lastname: Schmidt-Arras
authors.forename: Ramiro Rodriguez
authors.initials: RR
authors.lastname: Limardo
authors.forename: Olivier
authors.initials: O
authors.lastname: Leclercq
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Obal
authors.forename: Eric
authors.initials: E
authors.lastname: Prina
authors.forename: Adrian G
authors.initials: AG
authors.lastname: Turjanski
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Späth
authors.forename: Alejandro
authors.initials: A
authors.lastname: Buschiazzo
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D020134:Catalytic Domain; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000737:chemistry*; D007700:Kinetics; D018320:Leishmania major / Q000201:enzymology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D017433:Protein Structure, Secondary; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D011725:Pyridines / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D040681:Structural Homology, Protein; D013816:Thermodynamics
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D015800:Protozoan Proteins; D011725:Pyridines; D020928:Mitogen-Activated Protein Kinases; C093642:SB 203580