3QS7

Crystal structure of a human Flt3 ligand-receptor ternary complex

Summary for 3QS7

• Entry DOI: 10.2210/pdb3qs7/pdb
• Related: 3QS9
• Descriptor: SL cytokine, FL cytokine receptor, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: immunoglobulin-like domain, four-helical bundle cytokine, cytokine-receptor complex, extracellular complex, receptor tyrosine kinase, cytokine-signaling protein complex, cytokine/signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 257438.08

Authors

Verstraete, K.,Savvides, S.N. (deposition date: 2011-02-19, release date: 2011-03-16, Last modification date: 2023-09-13)

Primary citation

Verstraete, K.,Vandriessche, G.,Januar, M.,Elegheert, J.,Shkumatov, A.V.,Desfosses, A.,Van Craenenbroeck, K.,Svergun, D.I.,Gutsche, I.,Vergauwen, B.,Savvides, S.N.
Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex.
Blood, 118:60-68, 2011

PubMed Abstract: The class III receptor tyrosine kinase (RTKIII) Fms-like tyrosine kinase receptor 3 (Flt3) and its cytokine ligand (FL) play central roles in hematopoiesis and the immune system, by establishing signaling cascades crucial for the development and homeostasis of hematopoietic progenitors and antigen-presenting dendritic cells. However, Flt3 is also one of the most frequently mutated receptors in hematologic malignancies and is currently a major prognostic factor and clinical target for acute myeloid leukemia. Here, we report the structural basis for the Flt3 ligand-receptor complex and unveil an unanticipated extracellular assembly unlike any other RTKIII/V complex characterized to date. FL induces dimerization of Flt3 via a remarkably compact binding epitope localized at the tip of extracellular domain 3 of Flt3, and it invokes a ternary complex devoid of homotypic receptor interactions. Comparisons of Flt3 with homologous receptors and available mutagenesis data for FL have allowed us to rationalize the unique features of the Flt3 extracellular assembly. Furthermore, thermodynamic dissection of complex formation points to a pronounced enthalpically driven binding event coupled to an entropic penalty. Together, our data suggest that the high-affinity Flt3:FL complex is driven in part by a single preformed binding epitope on FL reminiscent of a "lock-and-key" binding mode, thereby setting the stage for antagonist design.

PubMed: 21389326
DOI: 10.1182/blood-2011-01-329532

Experimental method

X-RAY DIFFRACTION (4.3 Å)