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Title: Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1

Abstract

Human indoleamine 2,3-dioxygenase 1 (hIDO1) is an attractive cancer immunotherapeutic target owing to its role in promoting tumoral immune escape. However, drug development has been hindered by limited structural information. Here, we report the crystal structures of hIDO1 in complex with its substrate, Trp, an inhibitor, epacadostat, and/or an effector, indole ethanol (IDE). The data reveal structural features of the active site (Sa) critical for substrate activation; in addition, they disclose a new inhibitor-binding mode and a distinct small molecule binding site (Si). Structure-guided mutation of a critical residue, F270, to glycine perturbs the Si site, allowing structural determination of an inhibitory complex, where both the Sa and Si sites are occupied by Trp. The Si site offers a novel target site for allosteric inhibitors and a molecular explanation for the previously baffling substrate-inhibition behavior of the enzyme. Taken together, the data open exciting new avenues for structure-based drug design.

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NSFNIH
OSTI Identifier:
1410687
Resource Type:
Journal Article
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 8; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Lewis-Ballester, Ariel, Pham, Khoa N., Batabyal, Dipanwita, Karkashon, Shay, Bonanno, Jeffrey B., Poulos, Thomas L., and Yeh, Syun-Ru. Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1. United States: N. p., 2017. Web. doi:10.1038/s41467-017-01725-8.
Lewis-Ballester, Ariel, Pham, Khoa N., Batabyal, Dipanwita, Karkashon, Shay, Bonanno, Jeffrey B., Poulos, Thomas L., & Yeh, Syun-Ru. Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1. United States. doi:10.1038/s41467-017-01725-8.
Lewis-Ballester, Ariel, Pham, Khoa N., Batabyal, Dipanwita, Karkashon, Shay, Bonanno, Jeffrey B., Poulos, Thomas L., and Yeh, Syun-Ru. Wed . "Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1". United States. doi:10.1038/s41467-017-01725-8.
@article{osti_1410687,
title = {Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1},
author = {Lewis-Ballester, Ariel and Pham, Khoa N. and Batabyal, Dipanwita and Karkashon, Shay and Bonanno, Jeffrey B. and Poulos, Thomas L. and Yeh, Syun-Ru},
abstractNote = {Human indoleamine 2,3-dioxygenase 1 (hIDO1) is an attractive cancer immunotherapeutic target owing to its role in promoting tumoral immune escape. However, drug development has been hindered by limited structural information. Here, we report the crystal structures of hIDO1 in complex with its substrate, Trp, an inhibitor, epacadostat, and/or an effector, indole ethanol (IDE). The data reveal structural features of the active site (Sa) critical for substrate activation; in addition, they disclose a new inhibitor-binding mode and a distinct small molecule binding site (Si). Structure-guided mutation of a critical residue, F270, to glycine perturbs the Si site, allowing structural determination of an inhibitory complex, where both the Sa and Si sites are occupied by Trp. The Si site offers a novel target site for allosteric inhibitors and a molecular explanation for the previously baffling substrate-inhibition behavior of the enzyme. Taken together, the data open exciting new avenues for structure-based drug design.},
doi = {10.1038/s41467-017-01725-8},
journal = {Nature Communications},
issn = {2041-1723},
number = 1,
volume = 8,
place = {United States},
year = {2017},
month = {11}
}