Signalling complexes at the cell-matrix interface. Hohenester Erhard Current opinion in structural biology The extracellular matrix critically controls cell behaviour. Many cell-matrix interactions are mediated by transmembrane receptors of the integrin family. In the last two years, the structural changes resulting from ligand binding to integrins α5β1, αvβ3 and αIIbβ3 have been mapped in unprecedented detail. The structure of integrin αXβ2 has revealed how ligand binding to the α I domain is transmitted to the rest of the ectodomain. The structural characterisation of the cytosolic regulator talin has been continued, revealing how the integrin binding site is blocked in auto-inhibited talin. Finally, structures of the discoidin domain receptors DDR1 and DDR2 have begun to reveal how these atypical receptor tyrosine kinases become activated by the major matrix component collagen. 10.1016/j.sbi.2014.08.009

Using synthetic peptides and recombinant collagen to understand DDR-collagen interactions. Chen Eric A,Lin Yu-Shan Biochimica et biophysica acta. Molecular cell research The discoidin domain receptors, DDR1 and DDR2, are a subfamily of receptor tyrosine kinases that are activated upon binding to collagen. DDR-collagen interactions play an important role in cell proliferation and migration. Over the past few decades, synthetic peptides and recombinant collagen have been developed as tools to study the biophysical characteristics of collagen and various protein-collagen interactions. Herein we review how these techniques have been used to understand DDR-collagen interactions. Using synthetic collagen-like peptides, the GVM-GFO motif has been found to be the major binding site on collagens II and III for DDR1 and DDR2. An X-ray co-crystal structure of the DDR2 DS domain bound to a synthetic collagen-like peptide containing the GVM-GFO motif further provides molecular details of the DDR-collagen interactions. Recombinant collagen has also been used to provide further validation of the GVM-GFO binding motif. Although GVM-GFO has been defined as the minimal binding site, in synthetic peptide studies at least two triplets N-terminal to the essential GVM-GFO binding motif in collagen III sequence are needed for DDR2 activation at high peptide concentrations. 10.1016/j.bbamcr.2019.03.005

Discoidin domain receptors: Micro insights into macro assemblies. Agarwal Gunjan,Smith Adam W,Jones Blain Biochimica et biophysica acta. Molecular cell research Assembly of cell-surface receptors into specific oligomeric states and/or clusters before and after ligand binding is an important feature governing their biological function. Receptor oligomerization can be mediated by specific domains of the receptor, ligand binding, configurational changes or other interacting molecules. In this review we summarize our understanding of the oligomeric state of discoidin domain receptors (DDR1 and DDR2), which belong to the receptor tyrosine kinase family (RTK). DDRs form an interesting system from an oligomerization perspective as their ligand collagen(s) can also undergo supramolecular assembly to form fibrils. Even though DDR1 and DDR2 differ in the domains responsible to form ligand-free dimers they share similarities in binding to soluble, monomeric collagen. However, only DDR1b forms globular clusters in response to monomeric collagen and not DDR2. Interestingly, both DDR1 and DDR2 are assembled into linear clusters by the collagen fibril. Formation of these clusters is important for receptor phosphorylation and is mediated in part by other membrane components. We summarize how the oligomeric status of DDRs shares similarities with other members of the RTK family and with collagen receptors. Unraveling the multiple macro-molecular configurations adopted by this receptor-ligand pair can provide novel insights into the intricacies of cell-matrix interactions. 10.1016/j.bbamcr.2019.06.010

A patent review of discoidin domain receptor 1 (DDR1) modulators (2014-present). Guo Jing,Zhang Zhen,Ding Ke Expert opinion on therapeutic patents : Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase. Upon collagen binding, DDR1 undergoes tyrosine autophosphorylation, which consequently triggers downstream genetic and cellular pathways and plays critical roles in the regulation of cellular morphogenesis, differentiation, proliferation, adhesion, migration, and invasion. Increasing evidence suggests the potential roles of DDR1 in various human diseases including cancer, fibrosis, atherosclerosis, and other inflammatory disorders. Modulating the activity of DDR1 may be considered as a new therapeutic strategy for human cancer and inflammation-related diseases.: This article summarizes current progress on the development of selective DDR1 inhibitors and their potential therapeutic application during the period from 2014 to 2019.: DDR1 is closely linked to a variety of human diseases, including fibrotic disorders, atherosclerosis, and cancer, etc. Thus, DDR1 has been considered as a new potential target for drug discovery. A number of DDR1 inhibitors has been identified in the past 5 years, but most of them display relatively broad inhibition across the kinome. New generation DDR1 inhibitors targeting the allosteric sites outside of the canonical ATP-binding pocket or extracellular domain (allosteric inhibitors) may offer a new opportunity for selective DDR1 inhibition therapy development. 10.1080/13543776.2020.1732925

DDR1 role in fibrosis and its pharmacological targeting. Moll Solange,Desmoulière Alexis,Moeller Marcus J,Pache Jean-Claude,Badi Laura,Arcadu Filippo,Richter Hans,Satz Alexander,Uhles Sabine,Cavalli Andrea,Drawnel Faye,Scapozza Leonardo,Prunotto Marco Biochimica et biophysica acta. Molecular cell research Discoidin domain receptor1 (DDR1) is a collagen activated receptor tyrosine kinase and an attractive anti-fibrotic target. Its expression is mainly limited to epithelial cells located in several organs including skin, kidney, liver and lung. DDR1's biology is elusive, with unknown downstream activation pathways; however, it may act as a mediator of the stromal-epithelial interaction, potentially controlling the activation state of the resident quiescent fibroblasts. Increased expression of DDR1 has been documented in several types of cancer and fibrotic conditions including skin hypertrophic scars, idiopathic pulmonary fibrosis, cirrhotic liver and renal fibrosis. The present review article focuses on: a) detailing the evidence for a role of DDR1 as an anti-fibrotic target in different organs, b) clarifying DDR1 tissue distribution in healthy and diseased tissues as well as c) exploring DDR1 protective mode of action based on literature evidence and co-authors experience; d) detailing pharmacological efforts attempted to drug this subtle anti-fibrotic target to date. 10.1016/j.bbamcr.2019.04.004