6vbn

From Proteopedia

Crystal Structure of hTDO2 bound to inhibitor GNE1

Structural highlights

6vbn is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.18Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

T23O_HUMAN Incorporates oxygen into the indole moiety of tryptophan. Has a broad specificity towards tryptamine and derivatives including D- and L-tryptophan, 5-hydroxytryptophan and serotonin (By similarity).

Publication Abstract from PubMed

A class of imidazoisoindole (III) heme-binding indoleamine-2,3-dioxygenase (IDO1) inhibitors were optimized via structure-based drug design into a series of tryptophan-2,3-dioxygenase (TDO)-selective inhibitors. Kynurenine pathway modulation was demonstrated in vivo, which enabled evaluation of TDO as a potential cancer immunotherapy target. As means of mitigating the risk of drug-drug interactions arising from cytochrome P450 inhibition, a novel property-based drug design parameter, herein referred to as the CYP Index, was implemented for the design of inhibitors with appreciable selectivity for TDO over CYP3A4. We anticipate the CYP Index will be a valuable design parameter for optimizing CYP inhibition of any small molecule inhibitor containing a Lewis basic motif capable of binding heme.

Implementation of the CYP Index for the Design of Selective Tryptophan-2,3-dioxygenase Inhibitors.,Parr BT, Pastor R, Sellers BD, Pei Z, Jaipuri FA, Castanedo GM, Gazzard L, Kumar S, Li X, Liu W, Mendonca R, Pavana RK, Potturi H, Shao C, Velvadapu V, Waldo JP, Wu G, Yuen PW, Zhang Z, Zhang Y, Harris SF, Oh AJ, DiPasquale A, Dement K, La H, Goon L, Gustafson A, VanderPorten EC, Mautino MR, Liu Y ACS Med Chem Lett. 2020 Mar 4;11(4):541-549. doi: 10.1021/acsmedchemlett.0c00004., eCollection 2020 Apr 9. PMID:32292562^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Parr BT, Pastor R, Sellers BD, Pei Z, Jaipuri FA, Castanedo GM, Gazzard L, Kumar S, Li X, Liu W, Mendonca R, Pavana RK, Potturi H, Shao C, Velvadapu V, Waldo JP, Wu G, Yuen PW, Zhang Z, Zhang Y, Harris SF, Oh AJ, DiPasquale A, Dement K, La H, Goon L, Gustafson A, VanderPorten EC, Mautino MR, Liu Y. Implementation of the CYP Index for the Design of Selective Tryptophan-2,3-dioxygenase Inhibitors. ACS Med Chem Lett. 2020 Mar 4;11(4):541-549. PMID:32292562 doi:10.1021/acsmedchemlett.0c00004