Identification of an allosteric binding site for RORγt inhibition

M. Scheepstra; S. Leysen; G. van Almen; J.R. Miller; J. Piesvaux; V. Kutilek; H. van Eenennaam; H. Zhang; K. Barr; S.  Nagpal; S.M. Soisson; M. Kornienko; K. Wiley; N. Elsen; S. Sharma; C.C. Correll; B.W. Trotter; M. Stelt, van der; A. Oubrie; C. Ottmann; G. Parthasarathy; L. Brunsveld

doi:10.1038/ncomms9833

Identification of an allosteric binding site for RORγt inhibition

M. Scheepstra, S. Leysen, G. van Almen, J.R. Miller, J. Piesvaux, V. Kutilek, H. van Eenennaam, H. Zhang, K. Barr, S. Nagpal, S.M. Soisson, M. Kornienko, K. Wiley, N. Elsen, S. Sharma, C.C. Correll, B.W. Trotter, M. Stelt, van der, A. Oubrie, C. OttmannG. Parthasarathy, L. Brunsveld

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Abstract

RORγt is critical for the differentiation and proliferation of Th17 cells associated with several chronic autoimmune diseases. We report the discovery of a novel allosteric binding site on the nuclear receptor RORγt. Co-crystallization of the ligand binding domain (LBD) of RORγt with a series of small-molecule antagonists demonstrates occupancy of a previously unreported allosteric binding pocket. Binding at this non-canonical site induces an unprecedented conformational reorientation of helix 12 in the RORγt LBD, which blocks cofactor binding. The functional consequence of this allosteric ligand-mediated conformation is inhibition of function as evidenced by both biochemical and cellular studies. RORγt function is thus antagonized in a manner molecularly distinct from that of previously described orthosteric RORγt ligands. This brings forward an approach to target RORγt for the treatment of Th17-mediated autoimmune diseases. The elucidation of an unprecedented modality of pharmacological antagonism establishes a mechanism for modulation of nuclear receptors.

Original language	English
Article number	9833
Pages (from-to)	1-10
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9833
Publication status	Published - 7 Dec 2015

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Scheepstra, M., Leysen, S., van Almen, G., Miller, J. R., Piesvaux, J., Kutilek, V., van Eenennaam, H., Zhang, H., Barr, K., Nagpal, S., Soisson, S. M., Kornienko, M., Wiley, K., Elsen, N., Sharma, S., Correll, C. C., Trotter, B. W., Stelt, van der, M., Oubrie, A., ... Brunsveld, L. (2015). Identification of an allosteric binding site for RORγt inhibition. Nature Communications, 6, 1-10. Article 9833. https://doi.org/10.1038/ncomms9833

@article{f4c8cf6105464579b75699ef0f295e00,

title = "Identification of an allosteric binding site for RORγt inhibition",

abstract = "RORγt is critical for the differentiation and proliferation of Th17 cells associated with several chronic autoimmune diseases. We report the discovery of a novel allosteric binding site on the nuclear receptor RORγt. Co-crystallization of the ligand binding domain (LBD) of RORγt with a series of small-molecule antagonists demonstrates occupancy of a previously unreported allosteric binding pocket. Binding at this non-canonical site induces an unprecedented conformational reorientation of helix 12 in the RORγt LBD, which blocks cofactor binding. The functional consequence of this allosteric ligand-mediated conformation is inhibition of function as evidenced by both biochemical and cellular studies. RORγt function is thus antagonized in a manner molecularly distinct from that of previously described orthosteric RORγt ligands. This brings forward an approach to target RORγt for the treatment of Th17-mediated autoimmune diseases. The elucidation of an unprecedented modality of pharmacological antagonism establishes a mechanism for modulation of nuclear receptors. ",

author = "M. Scheepstra and S. Leysen and {van Almen}, G. and J.R. Miller and J. Piesvaux and V. Kutilek and {van Eenennaam}, H. and H. Zhang and K. Barr and S. Nagpal and S.M. Soisson and M. Kornienko and K. Wiley and N. Elsen and S. Sharma and C.C. Correll and B.W. Trotter and {Stelt, van der}, M. and A. Oubrie and C. Ottmann and G. Parthasarathy and L. Brunsveld",

year = "2015",

month = dec,

day = "7",

doi = "10.1038/ncomms9833",

language = "English",

volume = "6",

pages = "1--10",

journal = "Nature Communications",

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publisher = "Nature Publishing Group",

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Scheepstra, M, Leysen, S, van Almen, G, Miller, JR, Piesvaux, J, Kutilek, V, van Eenennaam, H, Zhang, H, Barr, K, Nagpal, S, Soisson, SM, Kornienko, M, Wiley, K, Elsen, N, Sharma, S, Correll, CC, Trotter, BW, Stelt, van der, M, Oubrie, A, Ottmann, C, Parthasarathy, G & Brunsveld, L 2015, 'Identification of an allosteric binding site for RORγt inhibition', Nature Communications, vol. 6, 9833, pp. 1-10. https://doi.org/10.1038/ncomms9833

TY - JOUR

T1 - Identification of an allosteric binding site for RORγt inhibition

AU - Scheepstra, M.

AU - Leysen, S.

AU - van Almen, G.

AU - Miller, J.R.

AU - Piesvaux, J.

AU - Kutilek, V.

AU - van Eenennaam, H.

AU - Zhang, H.

AU - Barr, K.

AU - Nagpal, S.

AU - Soisson, S.M.

AU - Kornienko, M.

AU - Wiley, K.

AU - Elsen, N.

AU - Sharma, S.

AU - Correll, C.C.

AU - Trotter, B.W.

AU - Stelt, van der, M.

AU - Oubrie, A.

AU - Ottmann, C.

AU - Parthasarathy, G.

AU - Brunsveld, L.

PY - 2015/12/7

Y1 - 2015/12/7

N2 - RORγt is critical for the differentiation and proliferation of Th17 cells associated with several chronic autoimmune diseases. We report the discovery of a novel allosteric binding site on the nuclear receptor RORγt. Co-crystallization of the ligand binding domain (LBD) of RORγt with a series of small-molecule antagonists demonstrates occupancy of a previously unreported allosteric binding pocket. Binding at this non-canonical site induces an unprecedented conformational reorientation of helix 12 in the RORγt LBD, which blocks cofactor binding. The functional consequence of this allosteric ligand-mediated conformation is inhibition of function as evidenced by both biochemical and cellular studies. RORγt function is thus antagonized in a manner molecularly distinct from that of previously described orthosteric RORγt ligands. This brings forward an approach to target RORγt for the treatment of Th17-mediated autoimmune diseases. The elucidation of an unprecedented modality of pharmacological antagonism establishes a mechanism for modulation of nuclear receptors.

AB - RORγt is critical for the differentiation and proliferation of Th17 cells associated with several chronic autoimmune diseases. We report the discovery of a novel allosteric binding site on the nuclear receptor RORγt. Co-crystallization of the ligand binding domain (LBD) of RORγt with a series of small-molecule antagonists demonstrates occupancy of a previously unreported allosteric binding pocket. Binding at this non-canonical site induces an unprecedented conformational reorientation of helix 12 in the RORγt LBD, which blocks cofactor binding. The functional consequence of this allosteric ligand-mediated conformation is inhibition of function as evidenced by both biochemical and cellular studies. RORγt function is thus antagonized in a manner molecularly distinct from that of previously described orthosteric RORγt ligands. This brings forward an approach to target RORγt for the treatment of Th17-mediated autoimmune diseases. The elucidation of an unprecedented modality of pharmacological antagonism establishes a mechanism for modulation of nuclear receptors.

U2 - 10.1038/ncomms9833

DO - 10.1038/ncomms9833

M3 - Article

C2 - 26640126

SN - 2041-1723

VL - 6

SP - 1

EP - 10

JO - Nature Communications

JF - Nature Communications

M1 - 9833

ER -

Identification of an allosteric binding site for RORγt inhibition

Abstract

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