Temporary Intermediates of L-Trp Along the Reaction Pathway of human Indoleamine 2,3-dioxygenase 1 and Identification of an Exo Site

Manon Mirgaux; Laurence Leherte; Johan Wouters

doi:10.1177/11786469211052964

Temporary Intermediates of L-Trp Along the Reaction Pathway of human Indoleamine 2,3-dioxygenase 1 and Identification of an Exo Site

Manon Mirgaux, Laurence Leherte, Johan Wouters

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Abstract

Protein dynamics governs most of the fundamental processes in the human body. Particularly, the dynamics of loops located near
an active site can be involved in the positioning of the substrate and the reaction mechanism. The understanding of the functioning of dynamic
loops is therefore a challenge, and often requires the use of a multi-disciplinary approach mixing, for example, crystallographic experiments
and molecular dynamics simulations. In the present work, the dynamic behavior of the JK-loop of the human indoleamine 2,3-dioxygenase 1
hemoprotein, a target for immunotherapy, is investigated. To overcome the lack of knowledge on this dynamism, the study reported here is based
on 3 crystal structures presenting different conformations of the loop, completed with molecular dynamics trajectories and MM-GBSA analyses,
in order to trace the reaction pathway of the enzyme. In addition, the crystal structures identify an exo site in the small unit of the enzyme, that
is populated redundantly by the substrate or the product of the reaction. The role of this newer reported exo site still needs to be investigated.

Original language	English
Pages (from-to)	1- 11
Journal	International Journal of Tryptophan Research
Volume	14
DOIs	https://doi.org/10.1177/11786469211052964
Publication status	Published - 15 Dec 2021

Keywords

Human indoleamine 2,3-dioxygenase 1
JK-loop dynamics
heme lability
L-Trp intermediates
molecular dynamics
protein crystallography

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10.1177/11786469211052964

Temporary Intermediates of L-Trp Along the Reaction Pathway of Human Indoleamine 2,3-Dioxygenase 1 and Identification of an Exo SiteFinal published version, 1.81 MBLicence: CC BY-NC

Cite this

@article{e266d9e3f0134aa5a7edd7e8f7e915bc,

title = "Temporary Intermediates of L-Trp Along the Reaction Pathway of human Indoleamine 2,3-dioxygenase 1 and Identification of an Exo Site",

abstract = "Protein dynamics governs most of the fundamental processes in the human body. Particularly, the dynamics of loops located nearan active site can be involved in the positioning of the substrate and the reaction mechanism. The understanding of the functioning of dynamicloops is therefore a challenge, and often requires the use of a multi-disciplinary approach mixing, for example, crystallographic experimentsand molecular dynamics simulations. In the present work, the dynamic behavior of the JK-loop of the human indoleamine 2,3-dioxygenase 1hemoprotein, a target for immunotherapy, is investigated. To overcome the lack of knowledge on this dynamism, the study reported here is basedon 3 crystal structures presenting different conformations of the loop, completed with molecular dynamics trajectories and MM-GBSA analyses,in order to trace the reaction pathway of the enzyme. In addition, the crystal structures identify an exo site in the small unit of the enzyme, thatis populated redundantly by the substrate or the product of the reaction. The role of this newer reported exo site still needs to be investigated.",

keywords = "Human indoleamine 2,3-dioxygenase 1, JK-loop dynamics, heme lability, L-Trp intermediates, molecular dynamics, protein crystallography",

author = "Manon Mirgaux and Laurence Leherte and Johan Wouters",

note = "Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: MM acknowledges the Fonds de la Recherche Scientifique (F.R.S.-FNRS, Belgium) for her Research Fellow grant. Funding Information: The authors thank the Soleil Synchrotron and the PROXIMA-1 and PROXIMA-2 beamlines staffs for the access to synchrotron-radiation facilities and for the precious advices during the experiment. The authors are also grateful to Professor Liang Tong for providing the hIDO1 plasmid. This research used the resources of the Plateforme Technologique de Calcul Intensif (PTCI; http://www.ptci.unamur.be) located at the University of Namur, Belgium, which is supported by the FNRS-FRFC, theWalloon Region and the University of Namur (Conventions Nos. 2.5020.11, GEQU.G006.15, 1610468, and RW/GEQ2016). The PTCI is a member of the Consortium des Equipements de Calcul Intensif (CECI). (http://www.ceci-hpc.be). The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: MM acknowledges the Fonds de la Recherche Scientifique (F.R.S.-FNRS, Belgium) for her Research Fellow grant. Funding Information: The authors thank the Soleil Synchrotron and the PROXIMA-1 and PROXIMA-2 beamlines staffs for the access to synchrotron-radiation facilities and for the precious advices during the experiment. The authors are also grateful to Professor Liang Tong for providing the hIDO1 plasmid. This research used the resources of the Plateforme Technologique de Calcul Intensif (PTCI; http://www.ptci.unamur.be ) located at the University of Namur, Belgium, which is supported by the FNRS-FRFC, theWalloon Region and the University of Namur (Conventions Nos. 2.5020.11, GEQU.G006.15, 1610468, and RW/GEQ2016). The PTCI is a member of the Consortium des Equipements de Calcul Intensif (CECI). ( http://www.ceci-hpc.be ). Publisher Copyright: {\textcopyright} The Author(s) 2021.",

year = "2021",

month = dec,

day = "15",

doi = "10.1177/11786469211052964",

language = "English",

volume = "14",

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T1 - Temporary Intermediates of L-Trp Along the Reaction Pathway of human Indoleamine 2,3-dioxygenase 1 and Identification of an Exo Site

AU - Mirgaux, Manon

AU - Leherte, Laurence

AU - Wouters, Johan

N1 - Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: MM acknowledges the Fonds de la Recherche Scientifique (F.R.S.-FNRS, Belgium) for her Research Fellow grant. Funding Information: The authors thank the Soleil Synchrotron and the PROXIMA-1 and PROXIMA-2 beamlines staffs for the access to synchrotron-radiation facilities and for the precious advices during the experiment. The authors are also grateful to Professor Liang Tong for providing the hIDO1 plasmid. This research used the resources of the Plateforme Technologique de Calcul Intensif (PTCI; http://www.ptci.unamur.be) located at the University of Namur, Belgium, which is supported by the FNRS-FRFC, theWalloon Region and the University of Namur (Conventions Nos. 2.5020.11, GEQU.G006.15, 1610468, and RW/GEQ2016). The PTCI is a member of the Consortium des Equipements de Calcul Intensif (CECI). (http://www.ceci-hpc.be). The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: MM acknowledges the Fonds de la Recherche Scientifique (F.R.S.-FNRS, Belgium) for her Research Fellow grant. Funding Information: The authors thank the Soleil Synchrotron and the PROXIMA-1 and PROXIMA-2 beamlines staffs for the access to synchrotron-radiation facilities and for the precious advices during the experiment. The authors are also grateful to Professor Liang Tong for providing the hIDO1 plasmid. This research used the resources of the Plateforme Technologique de Calcul Intensif (PTCI; http://www.ptci.unamur.be ) located at the University of Namur, Belgium, which is supported by the FNRS-FRFC, theWalloon Region and the University of Namur (Conventions Nos. 2.5020.11, GEQU.G006.15, 1610468, and RW/GEQ2016). The PTCI is a member of the Consortium des Equipements de Calcul Intensif (CECI). ( http://www.ceci-hpc.be ). Publisher Copyright: © The Author(s) 2021.

PY - 2021/12/15

Y1 - 2021/12/15

N2 - Protein dynamics governs most of the fundamental processes in the human body. Particularly, the dynamics of loops located nearan active site can be involved in the positioning of the substrate and the reaction mechanism. The understanding of the functioning of dynamicloops is therefore a challenge, and often requires the use of a multi-disciplinary approach mixing, for example, crystallographic experimentsand molecular dynamics simulations. In the present work, the dynamic behavior of the JK-loop of the human indoleamine 2,3-dioxygenase 1hemoprotein, a target for immunotherapy, is investigated. To overcome the lack of knowledge on this dynamism, the study reported here is basedon 3 crystal structures presenting different conformations of the loop, completed with molecular dynamics trajectories and MM-GBSA analyses,in order to trace the reaction pathway of the enzyme. In addition, the crystal structures identify an exo site in the small unit of the enzyme, thatis populated redundantly by the substrate or the product of the reaction. The role of this newer reported exo site still needs to be investigated.

AB - Protein dynamics governs most of the fundamental processes in the human body. Particularly, the dynamics of loops located nearan active site can be involved in the positioning of the substrate and the reaction mechanism. The understanding of the functioning of dynamicloops is therefore a challenge, and often requires the use of a multi-disciplinary approach mixing, for example, crystallographic experimentsand molecular dynamics simulations. In the present work, the dynamic behavior of the JK-loop of the human indoleamine 2,3-dioxygenase 1hemoprotein, a target for immunotherapy, is investigated. To overcome the lack of knowledge on this dynamism, the study reported here is basedon 3 crystal structures presenting different conformations of the loop, completed with molecular dynamics trajectories and MM-GBSA analyses,in order to trace the reaction pathway of the enzyme. In addition, the crystal structures identify an exo site in the small unit of the enzyme, thatis populated redundantly by the substrate or the product of the reaction. The role of this newer reported exo site still needs to be investigated.

KW - Human indoleamine 2,3-dioxygenase 1

KW - JK-loop dynamics

KW - heme lability

KW - L-Trp intermediates

KW - molecular dynamics

KW - protein crystallography

UR - http://www.scopus.com/inward/record.url?scp=85121558630&partnerID=8YFLogxK

U2 - 10.1177/11786469211052964

DO - 10.1177/11786469211052964

M3 - Article

VL - 14

SP - 1

EP - 11

JO - International Journal of Tryptophan Research

JF - International Journal of Tryptophan Research

ER -

Temporary Intermediates of L-Trp Along the Reaction Pathway of human Indoleamine 2,3-dioxygenase 1 and Identification of an Exo Site

Abstract

Keywords

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Human indoleamine-2,3-dioxygenase 2 cofactor lability and low substrate affinity explained by homology modeling, molecular dynamics and molecular docking

Cancer immunotherapy and dual IDO/TDO inhibitors: design, synthesis, physico-chemical and biological characterizations

CÉCI – Consortium of high performance computing centers

High Performance Computing Technology Platform

Physical Chemistry and characterization(PC2)

Crystal structure of L-Trp/Indoleamine 2,3-dioxygenagse 1 (hIDO1) complex with the JK-loop refined in the open conformation

Crystal structure of L-Trp/Indoleamine 2,3-dioxygenase (hIDO1) complex with the JK-loop refined in the intermediate conformation

Crystal structure of L-Trp/Indoleamine 2,3-dioxygenagse 1 (hIDO1) complex with the JK-loop refined in the closed conformation

Cite this

Temporary Intermediates of L-Trp Along the Reaction Pathway of human Indoleamine 2,3-dioxygenase 1 and Identification of an Exo Site

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Keywords

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