Advertisement

Topics

Ligand binding effects on the activation of the EGFR extracellular domain.

08:00 EDT 1st April 2019 | BioPortfolio

Summary of "Ligand binding effects on the activation of the EGFR extracellular domain."

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.

Affiliation

Journal Details

This article was published in the following journal.

Name: Physical chemistry chemical physics : PCCP
ISSN: 1463-9084
Pages:

Links

DeepDyve research library

PubMed Articles [27161 Associated PubMed Articles listed on BioPortfolio]

Syndecan transmembrane domain modulates intracellular signaling by regulating the oligomeric status of the cytoplasmic domain.

Cell surface receptors must specifically recognize an extracellular ligand and then trigger an appropriate response within the cell. Their general structure enables this, as it comprises an extracellu...

Ligand Density and Nanoparticle Clustering Cooperate in the Multivalent Amplification of Epidermal Growth Factor Receptor Activation.

Multivalent presentation of ligands on nanoparticles (NP) is considered a general strategy for enhancing receptor binding and activation through amplification of ligand-receptor interactions within th...

EpCAM ectodomain EpEX is a ligand of EGFR that counteracts EGF-mediated epithelial-mesenchymal transition through modulation of phospho-ERK1/2 in head and neck cancers.

Head and neck squamous cell carcinomas (HNSCCs) are characterized by outstanding molecular heterogeneity that results in severe therapy resistance and poor clinical outcome. Inter- and intratumoral he...

Synthesis, Characterization and Evaluation of Near-IR Boron Dipyrromethene (BODIPY) Bioconjugates for Labeling of Adenocarcinomas by Selectively Targeting the Epidermal Growth Factor Receptor (EGFR).

A series of five boron dipyrromethene (BODIPY) bioconjugates containing an EGFR-targeted pegylated LARLLT peptide and/or an α-D-glucopyranose or biotin ethylene diamine group were synthesized and the...

Engineered biosensors from dimeric ligand-binding domains.

Biosensors are important components of many synthetic biology and metabolic engineering applications. Here, we report a second generation of Saccharomyces cerevisiae digoxigenin and progesterone biose...

Clinical Trials [4192 Associated Clinical Trials listed on BioPortfolio]

Chimeric Switch Receptor Modified T Cells for Patients With PD-L1+ Recurrent or Metastatic Malignant Tumors

A Chimeric Switch Receptor, which was constructed by fusing the PD1 extracellular ligand binding domain to the CD28 intracellular costimulatory domain, was designed to target PD-L 1 positi...

Pilot Study of Autologous Anti-EGFRvIII CAR T Cells in Recurrent Glioblastoma Multiforme

Chimeric antigen receptor (CAR)-modified T cells can mediate long-term durable remissions in recurrent or refractory CD19+ B cell malignancies, and are a promising therapy to treat gliobla...

Effect of Aflibercept (Eylea®) in the Management of Bevacizumab (Avastin®) Resistant Diabetic Macular Edema

Multicenter randomized trials have demonstrated the safety and efficacy of intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents for the treatment of diabetic macular ede...

Phase II Study of Afatinib as Third- or Further-line Treatment for Patients With Stage IV Bronchial Adenocarcinoma, Harboring Wild-type EGFR, Expressing the Neurotensin - Neurotensin Receptor Complex

Lung cancer is the leading cause of cancer deaths in France, Europe and the world. 50% of lung cancers are of the adenocarcinoma subtype. 60% of patients present with a metastatic disease ...

Phase III Study (Tarceva®) vs Chemotherapy to Treat Advanced Non-Small Cell Lung Cancer (NSCLC) in Patients With Mutations in the TK Domain of EGFR

A Phase III, multicenter, open-label, randomized trial of Erlotinib (Tarceva®) versus chemotherapy in patients with advanced NSCLC with mutations in the Tyrosine Kinase (TK) domain ...

Medical and Biotech [MESH] Definitions

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.

Advertisement
Quick Search
Advertisement
Advertisement

 


DeepDyve research library

Relevant Topics

Cancer
  Bladder Cancer Brain Cancer Breast Cancer Cancer Cervical Cancer Colorectal Head & Neck Cancers Hodgkin Lymphoma Leukemia Lung Cancer Melanoma Myeloma Ovarian Cancer Pancreatic Cancer ...

Nutrition
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...

Drug Discovery
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...


Searches Linking to this Article