The crystal structure of the MAP kinase LmaMPK10 from leishmania major reveals parasite-specific features and regulatory mechanisms
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, structu...
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paper:paper_09692126_v20_n10_p1649_Horjales2023-06-08T15:59:01Z The crystal structure of the MAP kinase LmaMPK10 from leishmania major reveals parasite-specific features and regulatory mechanisms Turjanski, Adrián Gustavo Buschiazzo, Alejandro 4 (4 fluorophenyl) 2 (4 methylsulfinylphenyl) 5 (4 pyridyl)imidazole mitogen activated protein kinase article carboxy terminal sequence catalysis crystal structure enzyme activation enzyme regulation enzyme structure Leishmania major nonhuman priority journal regulatory mechanism Amino Acid Sequence Amino Acid Substitution Catalytic Domain Conserved Sequence Crystallography, X-Ray Hydrogen Bonding Imidazoles Kinetics Leishmania major Mitogen-Activated Protein Kinases Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed Protein Binding Protein Kinase Inhibitors Protein Structure, Secondary Protozoan Proteins Pyridines Sequence Homology, Amino Acid Structural Homology, Protein Thermodynamics Leishmania major Mammalia Trypanosomatidae 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. © 2012 Elsevier Ltd. Fil:Turjanski, A.G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Buschiazzo, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2012 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09692126_v20_n10_p1649_Horjales http://hdl.handle.net/20.500.12110/paper_09692126_v20_n10_p1649_Horjales |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
4 (4 fluorophenyl) 2 (4 methylsulfinylphenyl) 5 (4 pyridyl)imidazole mitogen activated protein kinase article carboxy terminal sequence catalysis crystal structure enzyme activation enzyme regulation enzyme structure Leishmania major nonhuman priority journal regulatory mechanism Amino Acid Sequence Amino Acid Substitution Catalytic Domain Conserved Sequence Crystallography, X-Ray Hydrogen Bonding Imidazoles Kinetics Leishmania major Mitogen-Activated Protein Kinases Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed Protein Binding Protein Kinase Inhibitors Protein Structure, Secondary Protozoan Proteins Pyridines Sequence Homology, Amino Acid Structural Homology, Protein Thermodynamics Leishmania major Mammalia Trypanosomatidae |
| spellingShingle |
4 (4 fluorophenyl) 2 (4 methylsulfinylphenyl) 5 (4 pyridyl)imidazole mitogen activated protein kinase article carboxy terminal sequence catalysis crystal structure enzyme activation enzyme regulation enzyme structure Leishmania major nonhuman priority journal regulatory mechanism Amino Acid Sequence Amino Acid Substitution Catalytic Domain Conserved Sequence Crystallography, X-Ray Hydrogen Bonding Imidazoles Kinetics Leishmania major Mitogen-Activated Protein Kinases Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed Protein Binding Protein Kinase Inhibitors Protein Structure, Secondary Protozoan Proteins Pyridines Sequence Homology, Amino Acid Structural Homology, Protein Thermodynamics Leishmania major Mammalia Trypanosomatidae Turjanski, Adrián Gustavo Buschiazzo, Alejandro The crystal structure of the MAP kinase LmaMPK10 from leishmania major reveals parasite-specific features and regulatory mechanisms |
| topic_facet |
4 (4 fluorophenyl) 2 (4 methylsulfinylphenyl) 5 (4 pyridyl)imidazole mitogen activated protein kinase article carboxy terminal sequence catalysis crystal structure enzyme activation enzyme regulation enzyme structure Leishmania major nonhuman priority journal regulatory mechanism Amino Acid Sequence Amino Acid Substitution Catalytic Domain Conserved Sequence Crystallography, X-Ray Hydrogen Bonding Imidazoles Kinetics Leishmania major Mitogen-Activated Protein Kinases Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed Protein Binding Protein Kinase Inhibitors Protein Structure, Secondary Protozoan Proteins Pyridines Sequence Homology, Amino Acid Structural Homology, Protein Thermodynamics Leishmania major Mammalia Trypanosomatidae |
| description |
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. © 2012 Elsevier Ltd. |
| author |
Turjanski, Adrián Gustavo Buschiazzo, Alejandro |
| author_facet |
Turjanski, Adrián Gustavo Buschiazzo, Alejandro |
| author_sort |
Turjanski, Adrián Gustavo |
| title |
The crystal structure of the MAP kinase LmaMPK10 from leishmania major reveals parasite-specific features and regulatory mechanisms |
| title_short |
The crystal structure of the MAP kinase LmaMPK10 from leishmania major reveals parasite-specific features and regulatory mechanisms |
| title_full |
The crystal structure of the MAP kinase LmaMPK10 from leishmania major reveals parasite-specific features and regulatory mechanisms |
| title_fullStr |
The crystal structure of the MAP kinase LmaMPK10 from leishmania major reveals parasite-specific features and regulatory mechanisms |
| title_full_unstemmed |
The crystal structure of the MAP kinase LmaMPK10 from leishmania major reveals parasite-specific features and regulatory mechanisms |
| title_sort |
crystal structure of the map kinase lmampk10 from leishmania major reveals parasite-specific features and regulatory mechanisms |
| publishDate |
2012 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09692126_v20_n10_p1649_Horjales http://hdl.handle.net/20.500.12110/paper_09692126_v20_n10_p1649_Horjales |
| work_keys_str_mv |
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| _version_ |
1768542187326275584 |