5EK3

Crystal structure of the indoleamine 2,3-dioxygenagse 1 (IDO1) complexed with NLG919 analogue

Summary for 5EK3

• Entry DOI: 10.2210/pdb5ek3/pdb
• Related: 5EK2 5EK4
• Descriptor: Indoleamine 2,3-dioxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, (1~{R})-1-cyclohexyl-2-[(5~{S})-5~{H}-imidazo[1,5-b]isoindol-5-yl]ethanol, ... (4 entities in total)
• Functional Keywords: inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 92566.16

Authors

Peng, Y.H.,Wu, J.S.,Wu, S.Y. (deposition date: 2015-11-03, release date: 2015-12-23, Last modification date: 2024-10-23)

Primary citation

Peng, Y.H.,Ueng, S.H.,Tseng, C.T.,Hung, M.S.,Song, J.S.,Wu, J.S.,Liao, F.Y.,Fan, Y.S.,Wu, M.H.,Hsiao, W.C.,Hsueh, C.C.,Lin, S.Y.,Cheng, C.Y.,Tu, C.H.,Lee, L.C.,Cheng, M.F.,Shia, K.S.,Shih, C.,Wu, S.Y.
Important Hydrogen Bond Networks in Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Design Revealed by Crystal Structures of Imidazoleisoindole Derivatives with IDO1
J.Med.Chem., 59:282-293, 2016

PubMed Abstract: Indoleamine 2,3-dioxygenase 1 (IDO1), promoting immune escape of tumors, is a therapeutic target for the cancer immunotherapy. A number of IDO1 inhibitors have been identified, but only limited structural biology studies of IDO1 inhibitors are available to provide insights on the binding mechanism of IDO1. In this study, we present the structure of IDO1 in complex with 24, a NLG919 analogue with potent activity. The complex structure revealed the imidazole nitrogen atom of 24 to coordinate with the heme iron, and the imidazoleisoindole core situated in pocket A with the 1-cyclohexylethanol moiety extended to pocket B to interact with the surrounding residues. Most interestingly, 24 formed an extensive hydrogen bond network with IDO1, which is a distinct feature of IDO1/24 complex structure and is not observed in the other IDO1 complex structures. Further structure-activity relationship, UV spectra, and structural biology studies of several analogues of 24 demonstrated that extensive hydrophobic interactions and the unique hydrogen bonding network contribute to the great potency of imidazoleisoindole derivatives. These results are expected to facilitate the structure-based drug design of new IDO inhibitors.

PubMed: 26642377
DOI: 10.1021/acs.jmedchem.5b01390

Experimental method

X-RAY DIFFRACTION (2.209 Å)