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5nu1

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Structural states of RORgt: X-ray elucidation of molecular mechanisms and binding interactions for natural and synthetic compounds

Structural highlights

5nu1 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 1.85Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RORG_HUMAN Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock.

Publication Abstract from PubMed

The T-cell-specific retinoic acid receptor (RAR)-related orphan receptor-gamma (RORgammat) is a key transcription factor for the production of pro-inflammatory Th17 cytokines, which are implicated in the pathogenesis of autoimmune diseases. Over the years, several structurally diverse RORgammat inverse agonists have been reported, but combining high potency and good physicochemical properties has remained a challenging task. We recently reported a new series of inverse agonists based on an imidazopyridine core with good physicochemical properties and excellent selectivity. Herein we report eight new X-ray crystal structures for different classes of natural and synthetic compounds, including examples selected from the patent literature. Analysis of their respective binding modes revealed insight into the molecular mechanisms that lead to agonism, antagonism, or inverse agonism. We report new molecular mechanisms for RORgammat agonism and propose a separation of the inverse agonists into two classes: those that act via steric clash and those that act via other mechanisms (for the latter, co-crystallization with a co-activator peptide and helix 12 in the agonist position is still possible). For the non-steric clash inverse agonists, we propose a new mechanism ("water trapping") which can be combined with other mechanisms (e.g., close contacts with H479). In addition, we compare the interactions made for selected compounds in the "back pocket" near S404 and in the "sulfate pocket" near R364 and R367. Taken together, these new mechanistic insights should prove useful for the design and optimization of further RORgammat modulators.

Structural States of RORgammat: X-ray Elucidation of Molecular Mechanisms and Binding Interactions for Natural and Synthetic Compounds.,Kallen J, Izaac A, Be C, Arista L, Orain D, Kaupmann K, Guntermann C, Hoegenauer K, Hintermann S ChemMedChem. 2017 Jul 6;12(13):1014-1021. doi: 10.1002/cmdc.201700278. Epub 2017 , Jun 20. PMID:28590087^[1]

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

References

↑ Kallen J, Izaac A, Be C, Arista L, Orain D, Kaupmann K, Guntermann C, Hoegenauer K, Hintermann S. Structural States of RORgammat: X-ray Elucidation of Molecular Mechanisms and Binding Interactions for Natural and Synthetic Compounds. ChemMedChem. 2017 Jul 6;12(13):1014-1021. doi: 10.1002/cmdc.201700278. Epub 2017 , Jun 20. PMID:28590087 doi:http://dx.doi.org/10.1002/cmdc.201700278