8R3F

C-terminal Rel-homology Domain of NFAT1

Summary for 8R3F

• Entry DOI: 10.2210/pdb8r3f/pdb
• Related: 8R07
• Descriptor: Nuclear factor of activated T-cells, cytoplasmic 2, (4~{S})-6-fluoranyl-3,4-dihydro-2~{H}-chromen-4-amine (3 entities in total)
• Functional Keywords: nfat1, transcription factor, fragment, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 24886.09

Authors

Zak, K.M.,Boettcher, J. (deposition date: 2023-11-08, release date: 2024-03-06, Last modification date: 2024-06-12)

Primary citation

Bottcher, J.,Fuchs, J.E.,Mayer, M.,Kahmann, J.,Zak, K.M.,Wunberg, T.,Woehrle, S.,Kessler, D.
Ligandability assessment of the C-terminal Rel-homology domain of NFAT1.
Arch Pharm, 357:e2300649-e2300649, 2024

PubMed Abstract: Transcription factors are generally considered challenging, if not "undruggable", targets but they promise new therapeutic options due to their fundamental involvement in many diseases. In this study, we aim to assess the ligandability of the C-terminal Rel-homology domain of nuclear factor of activated T cells 1 (NFAT1), a TF implicated in T-cell regulation. Using a combination of experimental and computational approaches, we demonstrate that small molecule fragments can indeed bind to this protein domain. The newly identified binder is the first small molecule binder to NFAT1 validated with biophysical methods and an elucidated binding mode by X-ray crystallography. The reported eutomer/distomer pair provides a strong basis for potential exploration of higher potency binders on the path toward degrader or glue modalities.

PubMed: 38396281
DOI: 10.1002/ardp.202300649

Experimental method

X-RAY DIFFRACTION (1.55 Å)