6OCX

Structure of human CIB1 in complex with peptide inhibitor UNC10245109

Summary for 6OCX

• Entry DOI: 10.2210/pdb6ocx/pdb
• Descriptor: Calcium and integrin-binding protein 1, Peptide inhibitor UNC10245109, CALCIUM ION, ... (4 entities in total)
• Functional Keywords: cib1, cancer, metal binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 94125.83

Authors

Puhl, A.C.,Godoy, A.S.,Pearce, K. (deposition date: 2019-03-25, release date: 2020-03-25, Last modification date: 2023-10-11)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.9 Å)