7nbi

Publication Abstract from PubMed

The overarching paradigm for the activation of class III and V receptor tyrosine kinases (RTKs) prescribes cytokine-mediated dimerization of the receptor ectodomains and homotypic receptor-receptor interactions. However, structural studies have shown that the hematopoietic receptor FLT3, a class III RTK, does not appear to engage in such receptor-receptor contacts, despite its efficient dimerization by dimeric FLT3 ligand (FL). As part of efforts to better understand the intricacies of FLT3 activation, we sought to engineer a monomeric FL. It was found that a Leu27Asp substitution at the dimer interface of the cytokine led to a stable monomeric cytokine (FLL27D) without abrogation of receptor binding. The crystal structure of FLL27D at 1.65 A resolution revealed that the introduced point mutation led to shielding of the hydrophobic footprint of the dimerization interface in wild-type FL without affecting the conformation of the FLT3 binding site. Thus, FLL27D can serve as a monomeric FL variant to further interrogate the assembly mechanism of extracellular complexes of FLT3 in physiology and disease.

Engineering and crystal structure of a monomeric FLT3 ligand variant.,Pannecoucke E, Raes L, Savvides SN Acta Crystallogr F Struct Biol Commun. 2021 Apr 1;77(Pt 4):121-127. doi:, 10.1107/S2053230X21003289. Epub 2021 Apr 6. PMID:33830077^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.