6t50

From Proteopedia

ROR(gamma)t ligand binding domain in complex with 25-hydroxycholesterol and allosteric ligand Glenmark

PDB ID 6t50

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Structural highlights

6t50 is a 1 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 1.87Å
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

Cooperative ligand binding is an important phenomenon in biological systems where ligand binding influences the binding of another ligand at an alternative site of the protein via an intramolecular network of interactions. The underlying mechanisms behind cooperative binding remain poorly understood, primarily due to the lack of structural data of these ternary complexes. Using time-resolved fluorescence resonance energy transfer (TR-FRET) studies, we show that cooperative ligand binding occurs for RORgammat, a nuclear receptor associated with the pathogenesis of autoimmune diseases. To provide the crucial structural insights, we solved 12 crystal structures of RORgammat simultaneously bound to various orthosteric and allosteric ligands. The presence of the orthosteric ligand induces a clamping motion of the allosteric pocket via helices 4 to 5. Additional molecular dynamics simulations revealed the unusual mechanism behind this clamping motion, with Ala355 shifting between helix 4 and 5. The orthosteric RORgammat agonists regulate the conformation of Ala355, thereby stabilizing the conformation of the allosteric pocket and cooperatively enhancing the affinity of the allosteric inverse agonists.

Cooperativity between the orthosteric and allosteric ligand binding sites of RORgammat.,de Vries RMJM, Meijer FA, Doveston RG, Leijten-van de Gevel IA, Brunsveld L Proc Natl Acad Sci U S A. 2021 Feb 9;118(6):e2021287118. doi: , 10.1073/pnas.2021287118. PMID:33536342^[1]

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

References

↑ de Vries RMJM, Meijer FA, Doveston RG, Leijten-van de Gevel IA, Brunsveld L. Cooperativity between the orthosteric and allosteric ligand binding sites of RORγt. Proc Natl Acad Sci U S A. 2021 Feb 9;118(6):e2021287118. PMID:33536342 doi:10.1073/pnas.2021287118