(alpha/beta+alpha)-peptide antagonists of BH3 domain/Bcl-x(L) recognition: toward general strategies for foldamer-based inhibition of protein-protein interactions.

(alpha/beta+alpha)-peptide antagonists of BH3 domain/Bcl-x(L) recognition: toward general strategies for foldamer-based inhibition of protein-protein interactions. Research Abstract Details 

Research Abstract Table of Contents

Jump to the:

(alpha/beta+alpha)-peptide antagonists of BH3 domain/Bcl-x(L) recognition: toward general strategies for foldamer-based inhibition of protein-protein interactions. Abstract Text:

Jack D Sadowsky,W Douglas Fairlie,Erik B Hadley,Hee-Seung Lee,Naoki Umezawa,Zaneta Nikolovska-Coleska,Shaomeng Wang,David C S Huang,York Tomita,Samuel H Gellman,

The development of molecules that bind to specific protein surface sites and inhibit protein-protein interactions is a fundamental challenge in molecular recognition. New strategies for approaching this challenge could have important long-term ramifications in biology and medicine. We are exploring the concept that unnatural oligomers with well-defined conformations ("foldamers") can mimic protein secondary structural elements and thereby block specific protein-protein interactions. Here, we describe the identification and analysis of helical peptide-based foldamers that bind to a specific cleft on the anti-apoptotic protein Bcl-xL by mimicking an alpha-helical BH3 domain. Initial studies, employing a fluorescence polarization (FP) competition assay, revealed that among several alpha/beta- and beta-peptide foldamer backbones only alpha/beta-peptides intended to adopt 14/15-helical secondary structure display significant binding to Bcl-xL. The most tightly binding Bcl-xL ligands are chimeric oligomers in which an N-terminal alpha/beta-peptide segment is fused to a C-terminal alpha-peptide segment ((alpha/beta + alpha)-peptides)). Sequence-affinity relationships were probed via standard and nonstandard techniques (alanine scanning and hydrophile scanning, respectively), and the results allowed us to construct a computational model of the ligand/Bcl-xL complex. Analytical ultracentrifugation with a high-affinity (alpha/beta + alpha)-peptide established 1:1 ligand:Bcl-xL stoichiometry under FP assay conditions. Binding selectivity studies with the most potent (alpha/beta + alpha)-peptide, conducted via surface plasmon resonance measurements, revealed that this ligand binds tightly to Bcl-w as well as to Bcl-xL, while binding to Bcl-2 is somewhat weaker. No binding could be detected with Mcl-1. We show that our most potent (alpha/beta + alpha)-peptide can induce cytochrome C release from mitochondria, an early step in apoptosis, in cell lysates, and that this activity is dependent upon inhibition of protein-protein interactions involving Bcl-xL.

(alpha/beta+alpha)-peptide antagonists of BH3 domain/Bcl-x(L) recognition: toward general strategies for foldamer-based inhibition of protein-protein interactions. Publishing Authors By Initials

JD Sadowsky,WD Fairlie,EB Hadley,HS Lee,N Umezawa,Z Nikolovska-Coleska,S Wang,DC Huang,Y Tomita,SH Gellman,

For similar peptides: intracellular signaling peptides and proteins: apoptosis regulatory proteins: proto-oncogene proteins c-bcl-2: bcl-x protein research abstracts see: peptides: intracellular signaling peptides and proteins: apoptosis regulatory proteins: proto-oncogene proteins c-bcl-2: bcl-x protein research

PUBMED ID PMID:

MEDLINE DATE:

(alpha/beta+alpha)-peptide antagonists of BH3 domain/Bcl-x(L) recognition: toward general strategies for foldamer-based inhibition of protein-protein interactions. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Journal of the American Chemical Society

VOLUME: 129

Page Numbers: 139-54

Journal Abbreviation: J. Am. Chem. Soc.

ISSN: 0002-7863

DAY: 10

MONTH: Jan

YEAR: 2007

(alpha/beta+alpha)-peptide antagonists of BH3 domain/Bcl-x(L) recognition: toward general strategies for foldamer-based inhibition of protein-protein interactions. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7503056

(alpha/beta+alpha)-peptide antagonists of BH3 domain/Bcl-x(L) recognition: toward general strategies for foldamer-based inhibition of protein-protein interactions. Keywords Mesh Terms:

KEYWORDS: bcl-X Protein

MESH TERMS: antagonists & inhibitors

Chemical & Substance for Abstract: (alpha/beta+alpha)-peptide antagonists of BH3 domain/Bcl-x(L) recognition: toward general strategies for foldamer-based inhibition of protein-protein interactions. Information

Substance Name: Cytochromes c

Registry Number: 9007-43-6

Grant and Affiliation Information for (alpha/beta+alpha)-peptide antagonists of BH3 domain/Bcl-x(L) recognition: toward general strategies for foldamer-based inhibition of protein-protein interactions.

AFFILIATION: Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, USA.

Country: United States

AGENCY: United States NIGMS

GRANT: GM56414

ACRONYM: GM

MEDLINETA: J Am Chem Soc

REFSOURCE:

DATABASENAME:

ACCESSION NUMBER:

Number Hits: 0

alpha/beta+alpha-peptide antagonists of BH3 domain/Bcl-xL recognition: toward general strategies for foldamer-based inhibition of protein-protein interactions Related Publications

• (alpha/beta+alpha)-peptide antagonists of BH3 domain/Bcl-x(L) recognition: toward general strategies for foldamer-based inhibition of protein-protein interactions.
• An antiparallel alpha-helical coiled-coil model system for rapid assessment of side-chain recognition at the hydrophobic interface.
• Backbone thioester exchange: a new approach to evaluating higher order structural stability in polypeptides.
• Chimeric (alpha/beta + alpha)-peptide ligands for the BH3-recognition cleft of Bcl-XL: critical role of the molecular scaffold in protein surface recognition.
• Crystallographic characterization of the alpha/beta-peptide 14/15-helix.
• Discrete heterogeneous quaternary structure formed by alpha/beta-peptide foldamers and alpha-peptides.
• Effect of certain detergents on sewage treatment.
• Effects of conformational stability and geometry of guanidinium display on cell entry by beta-peptides.
• Enantioselective organocatalytic Michael additions of aldehydes to enones with imidazolidinones: cocatalyst effects and evidence for an enamine intermediate.
• Enantioselective organocatalytic aminomethylation of aldehydes: a role for ionic interactions and efficient access to beta2-amino acids.
• Environment-independent 14-helix formation in short beta-peptides: striking a balance between shape control and functional diversity.
• Exploration of backbone space in foldamers containing alpha- and beta-amino acid residues: developing protease-resistant oligomers that bind tightly to the BH3-recognition cleft of Bcl-xL.
• HeLa cell entry by guanidinium-rich beta-peptides: importance of specific cation-cell surface interactions.
• Hydrophobic core repacking in a coiled-coil dimer via phage display: insights into plasticity and specificity at a protein-protein interface.
• Interplay among folding, sequence, and lipophilicity in the antibacterial and hemolytic activities of alpha/beta-peptides.
• Mimicry of antimicrobial host-defense peptides by random copolymers.
• Origins of the high 14-helix propensity of cyclohexyl-rigidified residues in beta-peptides.
• Practical synthesis of enantiomerically pure beta2-amino acids via proline-catalyzed diastereoselective aminomethylation of aldehydes.
• Preferred side-chain constellations at antiparallel coiled-coil interfaces.
• Residue requirements for helical folding in short alpha/beta-peptides: crystallographic characterization of the 11-helix in an optimized sequence.
• Roles of salt and conformation in the biological and physicochemical behavior of protegrin-1 and designed analogues: correlation of antimicrobial, hemolytic, and lipid bilayer-perturbing activities.
• Secondary structural preferences of 2,2-disubstituted pyrrolidine-4-carboxylic acid oligomers: beta-peptide foldamers that cannot form internal hydrogen bonds.
• Stabilizing and destabilizing effects of phenylalanine --> F5-phenylalanine mutations on the folding of a small protein.
• Structure-activity studies of 14-helical antimicrobial beta-peptides: probing the relationship between conformational stability and antimicrobial potency.
• Targeting protein-protein interactions: lessons from p53/MDM2.
• Thermodynamic analysis of autonomous parallel beta-sheet formation in water.
• Thermodynamic analysis of beta-sheet secondary structure by backbone thioester exchange.
• Tolerance of acyclic residues in the beta-peptide 12-helix: access to diverse side-chain arrays for biological applications.
• Translocation of a beta-peptide across cell membranes.
• Unexpected relationships between structure and function in alpha,beta-peptides: antimicrobial foldamers with heterogeneous backbones.