7utg

From Proteopedia

2D9 nanobody to BCL11A-exZF23 fragment

Structural highlights

7utg is a 1 chain structure with sequence from Vicugna pacos. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.25Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

Proximity-based strategies to degrade proteins have enormous therapeutic potential in medicine, but the technologies are limited to proteins for which small molecule ligands exist. The identification of such ligands for therapeutically relevant but "undruggable" proteins remains challenging. Herein, we employed yeast surface display of synthetic nanobodies to identify a protein ligand selective for BCL11A, a critical repressor of fetal globin gene transcription. Fusion of the nanobody to a cell-permeant miniature protein and an E3 adaptor creates a degrader that depletes cellular BCL11A in differentiated primary erythroid precursor cells, thereby inducing the expression of fetal hemoglobin, a modifier of clinical severity of sickle cell disease and beta-thalassemia. Our strategy provides a means of fetal hemoglobin induction through reversible, temporal modulation of BCL11A. Additionally, it establishes a new paradigm for the targeted degradation of previously intractable proteins.

A Cell-Permeant Nanobody-Based Degrader That Induces Fetal Hemoglobin.,Shen F, Zheng G, Setegne M, Tenglin K, Izadi M, Xie H, Zhai L, Orkin SH, Dassama LMK ACS Cent Sci. 2022 Dec 28;8(12):1695-1703. doi: 10.1021/acscentsci.2c00998. Epub , 2022 Dec 14. PMID:36589886^[1]

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

References

↑ Shen F, Zheng G, Setegne M, Tenglin K, Izadi M, Xie H, Zhai L, Orkin SH, Dassama LMK. A Cell-Permeant Nanobody-Based Degrader That Induces Fetal Hemoglobin. ACS Cent Sci. 2022 Dec 28;8(12):1695-1703. PMID:36589886 doi:10.1021/acscentsci.2c00998