4G35

Mcl-1 in complex with a biphenyl cross-linked Noxa peptide.

Summary for 4G35

• Entry DOI: 10.2210/pdb4g35/pdb
• Related PRD ID: PRD_000921
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1 homolog, Noxa BH3 peptide (cysteine-mediated cross-linked), 4,4'-bis(bromomethyl)biphenyl, ... (4 entities in total)
• Functional Keywords: apoptosis, bh3 domain, bcl-2 family, apoptosis-inhibitor complex, apoptosis/inhibitor
• Biological source: Mus musculus (mouse); More
• Cellular location: Membrane; Single-pass membrane protein (By similarity): P97287
• Total number of polymer chains: 2
• Total formula weight: 21158.78

Authors

Drake, E.,Edwardraja, S.,Lin, Q.,Gulick, A.M. (deposition date: 2012-07-13, release date: 2012-12-05, Last modification date: 2013-06-26)

Primary citation

Muppidi, A.,Doi, K.,Edwardraja, S.,Drake, E.J.,Gulick, A.M.,Wang, H.G.,Lin, Q.
Rational design of proteolytically stable, cell-permeable peptide-based selective Mcl-1 inhibitors.
J.Am.Chem.Soc., 134:14734-14737, 2012

PubMed Abstract: Direct chemical modifications provide a simple and effective means to "translate" bioactive helical peptides into potential therapeutics targeting intracellular protein-protein interactions. We previously showed that distance-matching bisaryl cross-linkers can reinforce peptide helices containing two cysteines at the i and i+7 positions and confer cell permeability to the cross-linked peptides. Here we report the first crystal structure of a biphenyl-cross-linked Noxa peptide in complex with its target Mcl-1 at 2.0 Å resolution. Guided by this structure, we remodeled the surface of this cross-linked peptide through side-chain substitution and N-methylation and obtained a pair of cross-linked peptides with substantially increased helicity, cell permeability, proteolytic stability, and cell-killing activity in Mcl-1-overexpressing U937 cells.

PubMed: 22920569
DOI: 10.1021/ja306864v

Experimental method

X-RAY DIFFRACTION (2 Å)