De novo designed transmembrane peptides activating the α5β1 integrin. 2018

Marco Mravic, and Hailin Hu, and Zhenwei Lu, and Joel S Bennett, and Charles R Sanders, and A Wayne Orr, and William F DeGrado
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.

Computationally designed transmembrane α-helical peptides (CHAMP) have been used to compete for helix-helix interactions within the membrane, enabling the ability to probe the activation of the integrins αIIbβ3 and αvβ3. Here, this method is extended towards the design of CHAMP peptides that inhibit the association of the α5β1 transmembrane (TM) domains, targeting the Ala-X3-Gly motif within α5. Our previous design algorithm was performed alongside a new workflow implemented within the widely used Rosetta molecular modeling suite. Peptides from each computational approach activated integrin α5β1 but not αVβ3 in human endothelial cells. Two CHAMP peptides were shown to directly associate with an α5 TM domain peptide in detergent micelles to a similar degree as a β1 TM peptide does. By solution-state nuclear magnetic resonance, one of these CHAMP peptides was shown to bind primarily the integrin β1 TM domain, which itself has a Gly-X3-Gly motif. The second peptide associated modestly with both α5 and β1 constructs, with slight preference for α5. Although the design goal was not fully realized, this work characterizes novel CHAMP peptides activating α5β1 that can serve as useful reagents for probing integrin biology.

UI MeSH Term Description Entries
D008823 Micelles Particles consisting of aggregates of molecules held loosely together by secondary bonds. The surface of micelles are usually comprised of amphiphatic compounds that are oriented in a way that minimizes the energy of interaction between the micelle and its environment. Liquids that contain large numbers of suspended micelles are referred to as EMULSIONS. Micelle
D010455 Peptides Members of the class of compounds composed of AMINO ACIDS joined together by peptide bonds between adjacent amino acids into linear, branched or cyclical structures. OLIGOPEPTIDES are composed of approximately 2-12 amino acids. Polypeptides are composed of approximately 13 or more amino acids. PROTEINS are considered to be larger versions of peptides that can form into complex structures such as ENZYMES and RECEPTORS. Peptide,Polypeptide,Polypeptides
D002462 Cell Membrane The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells. Plasma Membrane,Cytoplasmic Membrane,Cell Membranes,Cytoplasmic Membranes,Membrane, Cell,Membrane, Cytoplasmic,Membrane, Plasma,Membranes, Cell,Membranes, Cytoplasmic,Membranes, Plasma,Plasma Membranes
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000072417 Protein Domains Discrete protein structural units that may fold independently of the rest of the protein and have their own functions. Peptide Domain,Protein Domain,Domain, Peptide,Domain, Protein,Domains, Peptide,Domains, Protein,Peptide Domains
D000072756 Protein Conformation, alpha-Helical A secondary structure of proteins that is a right-handed helix or coil, where each amino (N-H) group of the peptide backbone contributes a hydrogen bond to the carbonyl(C alpha-Helical Conformation, Protein,alpha-Helical Protein Conformation,alpha-Helical Structures,alpha-Helices,alpha-Helix,Conformation, Protein alpha-Helical,Conformation, alpha-Helical Protein,Conformations, Protein alpha-Helical,Conformations, alpha-Helical Protein,Protein Conformation, alpha Helical,Protein Conformations, alpha-Helical,alpha Helical Conformation, Protein,alpha Helical Protein Conformation,alpha Helical Structures,alpha Helices,alpha Helix,alpha-Helical Conformations, Protein,alpha-Helical Protein Conformations,alpha-Helical Structure
D000595 Amino Acid Sequence The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION. Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D017076 Computer-Aided Design The use of computers for designing and/or manufacturing of anything, including drugs, surgical procedures, orthotics, and prosthetics. CAD-CAM,Computer-Aided Manufacturing,Computer-Assisted Design,Computer-Assisted Manufacturing,Computer Aided Design,Computer Aided Manufacturing,Computer Assisted Design,Computer Assisted Manufacturing,Computer-Aided Designs,Computer-Assisted Designs,Design, Computer-Aided,Design, Computer-Assisted,Designs, Computer-Aided,Designs, Computer-Assisted,Manufacturing, Computer-Aided,Manufacturing, Computer-Assisted
D039081 Integrin alpha5beta1 An integrin found in FIBROBLASTS; PLATELETS; MONOCYTES, and LYMPHOCYTES. Integrin alpha5beta1 is the classical receptor for FIBRONECTIN, but it also functions as a receptor for LAMININ and several other EXTRACELLULAR MATRIX PROTEINS. Receptors, VLA-5,Fibronectin Receptor,Integrin alpha-5 beta-1,Platelet Glycoprotein Ic-IIa,VLA-5,VLA-5 Receptors,Glycoprotein Ic-IIa, Platelet,Ic-IIa, Platelet Glycoprotein,Integrin alpha 5 beta 1,Platelet Glycoprotein Ic IIa,Receptor, Fibronectin,Receptors, VLA 5,VLA 5 Receptors,alpha-5 beta-1, Integrin,alpha5beta1, Integrin,beta-1, Integrin alpha-5

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