Structural Basis for Allosteric Ligand Recognition in the Human CC Chemokine Receptor 7
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The detailed structure of a protein implicated in cancer metastasis has revealed several promising new therapeutic leads.
Cancer cells can spread through the body via the lymphatic system and establish secondary tumours, which are responsible for about 90% of cancer deaths.
Now, a team co-led by Roche scientists has used X-ray crystallography to elucidate the structure of CC chemokine receptor 7 (CCR7) — a protein involved in helping cancer cells spread to the lymph nodes.
They also mapped the structure of CCR7 bound to an antagonist molecule and then searched computationally for drugs with similar three-dimensional shapes and other design features. One of the top matches was navarixin, a multi-target inhibitor with demonstrated anti-metastatic activity in clinical trials of patients with aggressive colon tumours. Navarixin is known to block other receptors, but CCR7 antagonism could explain part of its mechanism as well.
The findings provide a platform for further investigations of possible CCR7 inhibitors.
- Cell 178, 1222–1230 (2019). doi: 10.1016/j.cell.2019.07.028
|F. Hoffmann-La Roche Ltd., Switzerland||0.58|
|Paul Scherrer Institute (PSI), Switzerland||0.35|
|Swiss Light Source (SLS), PSI, Switzerland||0.05|
|Chugai Pharmaceutical Co., Ltd., Japan||0.03|