5C3G

Crystal structure of Bcl-xl bound to BIM-MM

Summary for 5C3G

• Entry DOI: 10.2210/pdb5c3g/pdb
• Descriptor: Bcl-2-like protein 1,Bcl-2-like protein 1, Bcl-2-like protein 11 (3 entities in total)
• Functional Keywords: complex, bcl-2 family, bh3, stapled peptide, apoptosis
• Biological source: Mus musculus (House Mouse); More
• Cellular location: Isoform Bcl-X(L): Mitochondrion inner membrane : Q07817; Endomembrane system ; Peripheral membrane protein . Isoform BimEL: Mitochondrion. Isoform BimL: Mitochondrion. Isoform BimS: Mitochondrion. Isoform Bim-alpha1: Mitochondrion: O43521
• Total number of polymer chains: 2
• Total formula weight: 20117.53

Authors

Miles, J.A.,Yeo, D.J.,Rowell, P.,Rodriguez-Marin, S.,Pask, C.M.,Warriner, S.L.,Edwards, T.A.,Wilson, A.J. (deposition date: 2015-06-17, release date: 2016-04-20, Last modification date: 2024-11-20)

Primary citation

Miles, J.A.,Yeo, D.J.,Rowell, P.,Rodriguez-Marin, S.,Pask, C.M.,Warriner, S.L.,Edwards, T.A.,Wilson, A.J.
Hydrocarbon constrained peptides - understanding preorganisation and binding affinity.
Chem Sci, 7:3694-3702, 2016

PubMed Abstract: The development of constrained peptides represents an emerging strategy to generate peptide based probes and hits for drug-discovery that address challenging protein-protein interactions (PPIs). In this manuscript we report on the use of a novel α-alkenylglycine derived amino acid to synthesise hydrocarbon constrained BH3-family sequences (BIM and BID). Our biophysical and structural analyses illustrate that whilst the introduction of the constraint increases the population of the bioactive α-helical conformation of the peptide in solution, it does not enhance the inhibitory potency against pro-apoptotic Bcl-x and Mcl-1 PPIs. SPR analyses indicate binding occurs an induced fit mechanism whilst X-ray analyses illustrate none of the key interactions between the helix and protein are disturbed. The behaviour derives from enthalpy-entropy compensation which may be considered in terms of the ground state energies of the unbound constrained and unconstrained peptides; this has implications for the design of preorganised peptides to target protein-protein interactions.

PubMed: 28970875
DOI: 10.1039/c5sc04048e

Experimental method

X-RAY DIFFRACTION (2.45 Å)