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The epidermal growth factor receptor (EGFR) is one of the most common target proteins in anti-cancer therapy. The binding of the EGF ligand to the EGFR extracellular domain (EGFR-ECD) promotes its inactive-to-active conformational transition (activation) but the relevant detailed mechanism remains elusive still. Here, the structural characterization and energetics of the EGFR-ECD conformational transition with and without the binding of the EGF are quantitatively explored using an innovative enhanced sampling MD simulation method. Intriguingly, the EGF offers hydrophobic interactions (e.g., EGF residues of Tyr44 and Leu47) and electrostatic interactions (e.g., the EGF residues of Glu5, Asp11, Asp17, and Arg41) to play a dominant role in dragging domain III to close the ligand binding domain gap. Subsequently, the correlation between domains III and II is enhanced through salt-bridges among Glu376, Arg403, and Arg405 from domain III and Glu293, Glu295, and Arg300 from domain II. Finally, the structural bending of domain II is regulated to facilitate the disengagement of domain II from domain IV. In this regard, the functional conformational transition of EGFR-ECD is a consequence of the cooperative motion of protein domains driven by the EGF ligand binding. The present study shows a detailed scenario of the EGF induced activation of EGFR-ECD and provides valuable information for drug discovery targeting the EGFR.
This article was published in the following journal.
Name: Physical chemistry chemical physics : PCCP
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A nuclear receptor protein which in humans is encoded by the RARA gene. It belongs to a family of transcription regulators of ligand-responsive regulatory proteins which include steroid hormone receptors. In addition to a C-terminal ligand-binding domain, these nuclear receptors contain a highly-conserved N-terminal zinc-finger domain that mediates binding ligand-responsive elements.
A cell surface receptor mediating cell adhesion to the EXTRACELLULAR MATRIX and to other cells via binding to LAMININ. It is involved in cell migration, embryonic development, leukocyte activation and tumor cell invasiveness. Integrin alpha6beta1 is the major laminin receptor on PLATELETS; LEUKOCYTES; and many EPITHELIAL CELLS, and ligand binding may activate a number of signal transduction pathways. Alternative splicing of the cytoplasmic domain of the alpha6 subunit (INTEGRIN ALPHA6) results in the formation of A and B isoforms of the heterodimer, which are expressed in a tissue-specific manner.
A family of conserved cell surface receptors that contain EPIDERMAL GROWTH FACTOR repeats in their extracellular domain and ANKYRIN repeats in their cytoplasmic domains. The cytoplasmic domain of notch receptors is released upon ligand binding and translocates to the CELL NUCLEUS where it acts as transcription factor.
A large, highly conserved, subfamily of ATP binding cassette transporters structurally characterized by a membrane-spanning domain composed of six ALPHA-HELICES, a large extracellular loop, nucleotide-binding domain, and a conserved cytoplasmic 80 amino acid sequence. In humans, it includes ABCA1(ATP BINDING CASSETTE TRANSPORTER 1) through ABCA10, as well as ABCA12 and ABCA13.
A class of proteins that were originally identified by their ability to bind the DNA sequence CCAAT. The typical CCAAT-enhancer binding protein forms dimers and consists of an activation domain, a DNA-binding basic region, and a leucine-rich dimerization domain (LEUCINE ZIPPERS). CCAAT-BINDING FACTOR is structurally distinct type of CCAAT-enhancer binding protein consisting of a trimer of three different subunits.
Bladder Cancer Brain Cancer Breast Cancer Cancer Cervical Cancer Colorectal Head & Neck Cancers Hodgkin Lymphoma Leukemia Lung Cancer Melanoma Myeloma Ovarian Cancer Pancreatic Cancer ...
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Clinical Approvals Clinical Trials Drug Approvals Drug Delivery Drug Discovery Generics Drugs Prescription Drugs In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are dis...