7NBI

Crystal structure of a monomeric FLT3 Ligand variant

Summary for 7NBI

• Entry DOI: 10.2210/pdb7nbi/pdb
• Descriptor: Fms-related tyrosine kinase 3 ligand, SULFATE ION (3 entities in total)
• Functional Keywords: flt3 ligand, engineered cytokine, monomeric flt3 ligand, de novo protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 32230.61

Authors

Pannecoucke, E.,Raes, L.,Savvides, S.N. (deposition date: 2021-01-26, release date: 2021-04-28, Last modification date: 2024-11-13)

Primary citation

Pannecoucke, E.,Raes, L.,Savvides, S.N.
Engineering and crystal structure of a monomeric FLT3 ligand variant.
Acta Crystallogr.,Sect.F, 77:121-127, 2021

PubMed Abstract: 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 (FL) without abrogation of receptor binding. The crystal structure of FL at 1.65 Å 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, FL can serve as a monomeric FL variant to further interrogate the assembly mechanism of extracellular complexes of FLT3 in physiology and disease.

PubMed: 33830077
DOI: 10.1107/S2053230X21003289

Experimental method

X-RAY DIFFRACTION (1.65 Å)