5FM2

Crystal structure of hyper-phosphorylated RET kinase domain with (proximal) juxtamembrane segment

Summary for 5FM2

• Entry DOI: 10.2210/pdb5fm2/pdb
• Related: 5FM3
• Descriptor: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET, 1-TER-BUTYL-3-P-TOLYL-1H-PYRAZOLO[3,4-D]PYRIMIDIN-4-YLAMINE (3 entities in total)
• Functional Keywords: transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 41002.75

Authors

Plaza-Menacho, I.,Barnouin, K.,Barry, R.,Borg, A.,Orme, M.,Mouilleron, S.,Martinez-Torres, R.J.,Meier, P.,McDonald, N.Q. (deposition date: 2015-10-30, release date: 2016-12-28, Last modification date: 2024-10-23)

Primary citation

Plaza-Menacho, I.,Barnouin, K.,Barry, R.,Borg, A.,Orme, M.,Chauhan, R.,Mouilleron, S.,Martinez-Torres, R.J.,Meier, P.,McDonald, N.Q.
RET Functions as a Dual-Specificity Kinase that Requires Allosteric Inputs from Juxtamembrane Elements.
Cell Rep, 17:3319-3332, 2016

PubMed Abstract: Receptor tyrosine kinases exhibit a variety of activation mechanisms despite highly homologous catalytic domains. Such diversity arises through coupling of extracellular ligand-binding portions with highly variable intracellular sequences flanking the tyrosine kinase domain and specific patterns of autophosphorylation sites. Here, we show that the juxtamembrane (JM) segment enhances RET catalytic domain activity through Y687. This phospho-site is also required by the JM region to rescue an otherwise catalytically deficient RET activation-loop mutant lacking tyrosines. Structure-function analyses identified interactions between the JM hinge, αC helix, and an unconventional activation-loop serine phosphorylation site that engages the HRD motif and promotes phospho-tyrosine conformational accessibility and regulatory spine assembly. We demonstrate that this phospho-S909 arises from an intrinsic RET dual-specificity kinase activity and show that an equivalent serine is required for RET signaling in Drosophila. Our findings reveal dual-specificity and allosteric components for the mechanism of RET activation and signaling with direct implications for drug discovery.

PubMed: 28009299
DOI: 10.1016/j.celrep.2016.11.061

Experimental method

X-RAY DIFFRACTION (3.3 Å)