6OD0

Structure of human CIB1 in complex with peptide inhibitor UNC10245092

6OD0 の概要

• エントリーDOI: 10.2210/pdb6od0/pdb
• 分子名称: Calcium and integrin-binding protein 1, Peptide inhibitor UNC10245092, CALCIUM ION, ... (4 entities in total)
• 機能のキーワード: cib1, cancer, metal binding protein
• 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: 46484.41

構造登録者

Puhl, A.C.,Godoy, A.S.,Pearce, K. (登録日: 2019-03-25, 公開日: 2020-03-25, 最終更新日: 2023-10-11)

主引用文献

Puhl, A.C.,Bogart, J.W.,Haberman, V.A.,Larson, J.E.,Godoy, A.S.,Norris-Drouin, J.L.,Cholensky, S.H.,Leisner, T.M.,Frye, S.V.,Parise, L.V.,Bowers, A.A.,Pearce, K.H.
Discovery and Characterization of Peptide Inhibitors for Calcium and Integrin Binding Protein 1.
Acs Chem.Biol., 15:1505-1516, 2020

PubMed Abstract: Calcium and integrin binding protein 1 (CIB1) is an EF-hand-containing, small intracellular protein that has recently been implicated in cancer cell survival and proliferation. In particular, CIB1 depletion significantly impairs tumor growth in triple-negative breast cancer (TNBC). Thus, CIB1 is a potentially attractive target for cancer chemotherapy that has yet to be validated by a chemical probe. To produce a probe molecule to the CIB1 helix 10 (H10) pocket and demonstrate that it is a viable target for molecular intervention, we employed random peptide phage display to screen and select CIB1-binding peptides. The top peptide sequence selected, UNC10245092, was produced synthetically, and binding to CIB1 was confirmed by isothermal titration calorimetry (ITC) and a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. Both assays showed that the peptide bound to CIB1 with low nanomolar affinity. CIB1 was cocrystallized with UNC10245092, and the 2.1 Å resolution structure revealed that the peptide binds as an α-helix in the H10 pocket, displacing the CIB1 C-terminal H10 helix and causing conformational changes in H7 and H8. UNC10245092 was further derivatized with a C-terminal Tat-derived cell penetrating peptide (CPP) to demonstrate its effects on TNBC cells in culture, which are consistent with results of CIB1 depletion. These studies provide a first-in-class chemical tool for CIB1 inhibition in cell culture and validate the CIB1 H10 pocket for future probe and drug discovery efforts.

PubMed: 32383857
DOI: 10.1021/acschembio.0c00144

実験手法

X-RAY DIFFRACTION (2.15 Å)