6ST2

Selective Affimers Recognize BCL-2 Family Proteins Through Non-Canonical Structural Motifs

6ST2 の概要

• エントリーDOI: 10.2210/pdb6st2/pdb
• 分子名称: Bcl-2-like protein 1, Affimer AF6, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: affimer, protein binding
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 56629.52

構造登録者

Hobor, F.,Miles, J.A.,Trinh, C.H.,Taylor, J.,Tiede, C.,Rowell, P.R.,Jackson, B.,Nadat, F.,Kyle, H.F.,Wicky, B.I.M.,Clarke, J.,Tomlinson, D.C.,Wilson, A.J.,Edwards, T.A. (登録日: 2019-09-09, 公開日: 2020-09-30, 最終更新日: 2024-01-24)

主引用文献

Miles, J.A.,Hobor, F.,Trinh, C.H.,Taylor, J.,Tiede, C.,Rowell, P.R.,Jackson, B.R.,Nadat, F.A.,Ramsahye, P.,Kyle, H.F.,Wicky, B.I.M.,Clarke, J.,Tomlinson, D.C.,Wilson, A.J.,Edwards, T.A.
Selective Affimers Recognise the BCL-2 Family Proteins BCL-x L and MCL-1 through Noncanonical Structural Motifs*.
Chembiochem, 22:232-240, 2021

PubMed Abstract: The BCL-2 family is a challenging group of proteins to target selectively due to sequence and structural homologies across the family. Selective ligands for the BCL-2 family regulators of apoptosis are useful as probes to understand cell biology and apoptotic signalling pathways, and as starting points for inhibitor design. We have used phage display to isolate Affimer reagents (non-antibody-binding proteins based on a conserved scaffold) to identify ligands for MCL-1, BCL-x , BCL-2, BAK and BAX, then used multiple biophysical characterisation methods to probe the interactions. We established that purified Affimers elicit selective recognition of their target BCL-2 protein. For anti-apoptotic targets BCL-x and MCL-1, competitive inhibition of their canonical protein-protein interactions is demonstrated. Co-crystal structures reveal an unprecedented mode of molecular recognition; where a BH3 helix is normally bound, flexible loops from the Affimer dock into the BH3 binding cleft. Moreover, the Affimers induce a change in the target proteins towards a desirable drug-bound-like conformation. These proof-of-concept studies indicate that Affimers could be used as alternative templates to inspire the design of selective BCL-2 family modulators and more generally other protein-protein interaction inhibitors.

PubMed: 32961017
DOI: 10.1002/cbic.202000585

実験手法

X-RAY DIFFRACTION (1.79 Å)