Lander, Alexander J., Kong, Yifu, Jin, Yi, Wu, Chuanliu and Luk, Louis Y. P.  ORCID: https://orcid.org/0000-0002-7864-6261
2024.
Deciphering the synthetic and refolding strategy of a cysteine-rich domain in the tumor necrosis factor receptor (TNF-R) for racemic crystallography analysis and d-peptide ligand discovery.
ACS Bio & Med Chem Au
4
(1)
, pp. 68-76.
10.1021/acsbiomedchemau.3c00060
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Abstract
Many cell-surface receptors are promising targets for chemical synthesis because of their critical roles in disease development. This synthetic approach enables investigations by racemic protein crystallography and ligand discovery by mirror-image methodologies. However, due to their complex nature, the chemical synthesis of a receptor can be a significant challenge. Here, we describe the chemical synthesis and folding of a central, cysteine-rich domain of the cell-surface receptor tumor necrosis factor 1 which is integral to binding of the cytokine TNF-α, namely, TNFR-1 CRD2. Racemic protein crystallography at 1.4 Å confirmed that the native binding conformation was preserved, and TNFR-1 CRD2 maintained its capacity to bind to TNF-α (KD ≈ 7 nM). Encouraged by this discovery, we carried out mirror-image phage display using the enantiomeric receptor mimic and identified a d-peptide ligand for TNFR-1 CRD2 (KD = 1 μM). This work demonstrated that cysteine-rich domains, including the central domains, can be chemically synthesized and used as mimics for investigations.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Chemistry |
| Publisher: | American Chemical Society |
| ISSN: | 2694-2437 |
| Funders: | BBSRC, Wellcome Trust |
| Date of First Compliant Deposit: | 14 December 2023 |
| Date of Acceptance: | 15 November 2023 |
| Last Modified: | 12 Aug 2024 09:26 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/164809 |
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