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Abstract:

Human indoleamine 2,3-dioxygenase catalyzes the oxidative cleavage of tryptophan to N-formyl kynurenine, the initial and rate-limiting step in the kynurenine pathway. Additionally, this enzyme has been identified as a possible target for cancer therapy. A 20-amino acid protein segment (the JK loop), which connects the J and K helices, was not resolved in the reported hIDO crystal structure. Previous studies have shown that this loop undergoes structural rearrangement upon substrate binding. In this work, we apply a combination of replica exchange molecular dynamics simulations and site-directed mutagenesis experiments to characterize the structure and dynamics of this protein region. Our simulations show that the JK loop can be divided into two regions: the first region (JK loopC) displays specific and well-defined conformations and is within hydrogen bonding distance of the substrate, while the second region (JK loopN) is highly disordered and exposed to the solvent. The peculiar flexible nature of JK loopN suggests that it may function as a target for post-translational modifications and/or a mediator for protein-protein interactions. In contrast, hydrogen bonding interactions are observed between the substrate and Thr379 in the highly conserved "GTGG" motif of JK loopC, thereby anchoring JK loopC in a closed conformation, which secures the appropriate substrate binding mode for catalysis. Site-directed mutagenesis experiments confirm the key role of this residue, highlighting the importance of the JK loopC conformation in regulating the enzymatic activity. Furthermore, the existence of the partially and totally open conformations in the substrate-free form suggests a role of JK loopC in controlling substrate and product dynamics. © 2016 American Chemical Society.

Registro:

Documento: Artículo
Título:Structural Study of a Flexible Active Site Loop in Human Indoleamine 2,3-Dioxygenase and Its Functional Implications
Autor:Álvarez, L.; Lewis-Ballester, A.; Roitberg, A.; Estrin, D.A.; Yeh, S.-R.; Marti, M.A.; Capece, L.
Filiación:Dto. de Química Inorgánica, Analítica y Química Física, Fac. de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, C1428EGA, Argentina
INQUIMAE-CONICET, Buenos Aires, C1428EGA, Argentina
Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, New York, NY 10461, United States
Department of Chemistry, University of Florida, 440 Leigh Hall, Gainesville, FL 32611-7200, United States
Dto. de Química Biologica Fac. de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, C1428EGA, Argentina
IQUIBICEN-CONICET, Buenos Aires C1428EGA, Argentina, Argentina
Palabras clave:Amino acids; Binding energy; Bins; Catalysis; Conformations; Enzyme activity; Hydrogen bonds; Molecular dynamics; Mutagenesis; Proteins; Hydrogen bonding interactions; Indoleamine 2 ,3-dioxygenase; Post-translational modifications; Protein-protein interactions; Replica-exchange molecular dynamics simulations; Site directed mutagenesis; Structural rearrangement; Structure and dynamics; Crystal structure; indoleamine 2,3 dioxygenase; kynurenine; tryptophan; indoleamine 2,3 dioxygenase; indoleamine 2,3-dioxygenase 1, human; Article; binding site; cancer therapy; catalyst; comparative study; conformational transition; crystal structure; enzyme activity; enzyme structure; human; hydrogen bond; molecular dynamics; priority journal; protein protein interaction; protein purification; protein secondary structure; signal transduction; site directed mutagenesis; static electricity; catalysis; chemistry; genetics; metabolism; protein domain; protein motif; structure activity relation; X ray crystallography; Amino Acid Motifs; Catalysis; Crystallography, X-Ray; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Mutagenesis, Site-Directed; Protein Domains; Structure-Activity Relationship
Año:2016
Volumen:55
Número:19
Página de inicio:2785
Página de fin:2793
DOI: http://dx.doi.org/10.1021/acs.biochem.6b00077
Título revista:Biochemistry
Título revista abreviado:Biochemistry
ISSN:00062960
CODEN:BICHA
CAS:indoleamine 2,3 dioxygenase; kynurenine, 16055-80-4, 343-65-7; tryptophan, 6912-86-3, 73-22-3; indoleamine 2,3-dioxygenase 1, human; Indoleamine-Pyrrole 2,3,-Dioxygenase
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062960_v55_n19_p2785_Alvarez

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Citas:

---------- APA ----------
Álvarez, L., Lewis-Ballester, A., Roitberg, A., Estrin, D.A., Yeh, S.-R., Marti, M.A. & Capece, L. (2016) . Structural Study of a Flexible Active Site Loop in Human Indoleamine 2,3-Dioxygenase and Its Functional Implications. Biochemistry, 55(19), 2785-2793.
http://dx.doi.org/10.1021/acs.biochem.6b00077
---------- CHICAGO ----------
Álvarez, L., Lewis-Ballester, A., Roitberg, A., Estrin, D.A., Yeh, S.-R., Marti, M.A., et al. "Structural Study of a Flexible Active Site Loop in Human Indoleamine 2,3-Dioxygenase and Its Functional Implications" . Biochemistry 55, no. 19 (2016) : 2785-2793.
http://dx.doi.org/10.1021/acs.biochem.6b00077
---------- MLA ----------
Álvarez, L., Lewis-Ballester, A., Roitberg, A., Estrin, D.A., Yeh, S.-R., Marti, M.A., et al. "Structural Study of a Flexible Active Site Loop in Human Indoleamine 2,3-Dioxygenase and Its Functional Implications" . Biochemistry, vol. 55, no. 19, 2016, pp. 2785-2793.
http://dx.doi.org/10.1021/acs.biochem.6b00077
---------- VANCOUVER ----------
Álvarez, L., Lewis-Ballester, A., Roitberg, A., Estrin, D.A., Yeh, S.-R., Marti, M.A., et al. Structural Study of a Flexible Active Site Loop in Human Indoleamine 2,3-Dioxygenase and Its Functional Implications. Biochemistry. 2016;55(19):2785-2793.
http://dx.doi.org/10.1021/acs.biochem.6b00077