TY - JOUR
T1 - Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase
AU - Lewis-Ballester, Ariel
AU - Pham, Khoa N.
AU - Batabyal, Dipanwita
AU - Karkashon, Shay
AU - Bonanno, Jeffrey B.
AU - Poulos, Thomas L.
AU - Yeh, Syun Ru
N1 - Funding Information:
S.-R.Y., A.L.-B., and K.N.P. thank Dr D.L. Rousseau for helpful discussions. The structural data of the Trp-complexes were collected at SSRL, a national user facility operated by Stanford University on behalf of the United States Department of Energy, Office of Basic Energy Sciences. The Stanford Synchrotron Radiation Lightsource Structural Molecular Biology Program is supported by the United States Department of Energy, Office of Biological and Environmental Research and by the National Center for Research Resources, Biomedical Technology Program, and NIGMS of the National Institutes of Health. The Einstein Crystallographic Core X-ray diffraction facility is supported by NIH Shared Instrumentation Grant S10 OD020068, which we gratefully acknowledge. The structural data of the epacadostat complex were collected by the LRL-CAT beamline staff at Sector 31 of the Advanced Photon Source. This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. Use of the Lilly Research Laboratories Collaborative Access Team (LRL-CAT) beamline at Sector 31 of the Advanced Photon Source was provided by Eli Lilly Company, which operates the facility. We acknowledge the contributions of Drs F. Forouhar, S. Lew, J. Seetharaman and L. Tong to the initial stages of this project. This work was supported by National Institute of Health Grant GM115773 and National Science Foundation Grant CHE-1404929 (to S.-R.Y.) and National Institute of Health Grant GM57353 (to T.L.P.).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-017-01725-8
DO - 10.1038/s41467-017-01725-8
M3 - Article
C2 - 29167421
AN - SCOPUS:85034859377
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1693
ER -
