Bayliss R , Choi J , Fennell DA , Fry AM , Richards MW .

12772 Cancer Research UK, 13-0042 Worldwide Cancer Research, 16-0119 Worldwide Cancer Research, C24461/A12772 Cancer Research UK

	Fig. 1. Overview of EML proteins. a Domain structure of human EML4 with structural features labelled. Primary (1°) sequence features are labelled in black: CC, coiled-coil; basic region; HELP, Hydrophobic motif found in EML proteins; WD repeats, Trp-Asp repeats. Tertiary (3°) structure features are labelled in red text: TD, trimerisation domain; TAPE, tandem atypical propeller domain found in EML proteins. The TAPE domain N-terminal region is coloured teal and the C-terminal region is coloured orange. b Speculative model of the overall trimeric architecture of the EML4 protein. Crystal structures of the EML4 TD (PDB code 4CGC [17]) and EML1 TAPE domain (PDB code 4CI8 [18]) are connected with dotted lines to show the basic region that is predicted to be unstructured. One protomer of the trimer is coloured using the scheme in 1a—this shows how the N- and C-terminal regions of the TAPE domain (teal and orange, respectively) come together to close the fold of this domain
	Fig. 2. Overview of ALK. a Domain structure of ALK with structural features labelled: MAM, Meprin, A5 protein and protein tyrosine phosphatase Mu domain; LDLa, Low-density lipoprotein receptor domain class A; G-rich, glycrine-rich region; TM, transmembrane helix; TK, tyrosine kinase domain. The interactions of upstream, extracellular signalling molecules with ALK are shown: pleiotrophin (PTN) and midkine (MK) as putative ligands in humans; jelly belly (Jeb) as a confirmed ligand in Drosophila. b Outline of oncogenic ALK signalling mechanisms. Crystal structure of ALK TK domain (PDB code 3LCT [32]) is shown as a cartoon representation, coloured magenta
	Fig. 3. Overview of EML4-ALK fusions and variants. a EML4-ALK fusion gene is generated by a paracentric inversion on the short arm of chromosome 2. Dotted lines indicate potential fusion sites. b Schematic illustrations of four major EML4-ALK variant proteins, showing where the ALK TK domain is inserted into the EML4 protein. c The individual subdomains that make up the TAPE domain of EML4 are shown. The two propellers of the TAPE domain have thirteen canonical blades and a non-canonical blade comprising the 12N and 12C subdomains. The positions of ALK TK domain insertion into the EML4 structure are shown as black squares, labelled with the variant number. Note that, with the exception of v3 and v5, all variants have ALK inserted into the TAPE domain
	Fig. 4. ALK tyrosine kinase inhibitors. Chemical structures of ALK TKIs are shown with the core scaffold highlighted in red. a diaminopyrimidine. b Aminopyridine. c Dihydrobenzocarbazole. d Crystal structure of ALK TK domain (pink cartoon) bound to crizotinib (beige spheres). The image is based on PDB code 2XP2 [71]. Key residues mutated in drug resistance ALK are shown as sticks, coloured teal

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