3LCS
Crystal Structure of the Anaplastic Lymphoma Kinase Catalytic Domain
Summary for 3LCS
| Entry DOI | 10.2210/pdb3lcs/pdb |
| Related | 3L9P 3LCT |
| Descriptor | ALK tyrosine kinase receptor, STAUROSPORINE, GLYCEROL, ... (4 entities in total) |
| Functional Keywords | kinase domain, atp-binding, glycoprotein, kinase, membrane, nucleotide-binding, phosphoprotein, proto-oncogene, receptor, transmembrane, tyrosine-protein kinase, transferase |
| Biological source | Homo sapiens (human) |
| Cellular location | Membrane; Single-pass type I membrane protein: Q9UM73 |
| Total number of polymer chains | 1 |
| Total formula weight | 39292.04 |
| Authors | Lee, C.C. (deposition date: 2010-01-11, release date: 2010-08-04, Last modification date: 2023-09-06) |
| Primary citation | Lee, C.C.,Jia, Y.,Li, N.,Sun, X.,Ng, K.,Ambing, E.,Gao, M.Y.,Hua, S.,Chen, C.,Kim, S.,Michellys, P.Y.,Lesley, S.A.,Harris, J.L.,Spraggon, G. Crystal structure of the ALK (anaplastic lymphoma kinase) catalytic domain. Biochem.J., 430:425-437, 2010 Cited by PubMed Abstract: ALK (anaplastic lymphoma kinase) is an RTK (receptor tyrosine kinase) of the IRK (insulin receptor kinase) superfamily, which share an YXXXYY autophosphorylation motif within their A-loops (activation loops). A common activation and regulatory mechanism is believed to exist for members of this superfamily typified by IRK and IGF1RK (insulin-like growth factor receptor kinase-1). Chromosomal translocations involving ALK were first identified in anaplastic large-cell lymphoma, a subtype of non-Hodgkin's lymphoma, where aberrant fusion of the ALK kinase domain with the NPM (nucleophosmin) dimerization domain results in autophosphosphorylation and ligand-independent activation. Activating mutations within the full-length ALK kinase domain, most commonly R1275Q and F1174L, which play a major role in neuroblastoma, were recently identified. To provide a structural framework for understanding these mutations and to guide structure-assisted drug discovery efforts, the X-ray crystal structure of the unphosphorylated ALK catalytic domain was determined in the apo, ADP- and staurosporine-bound forms. The structures reveal a partially inactive protein kinase conformation distinct from, and lacking, many of the negative regulatory features observed in inactive IGF1RK/IRK structures in their unphosphorylated forms. The A-loop adopts an inhibitory pose where a short proximal A-loop helix (alphaAL) packs against the alphaC helix and a novel N-terminal beta-turn motif, whereas the distal portion obstructs part of the predicted peptide-binding region. The structure helps explain the reported unique peptide substrate specificity and the importance of phosphorylation of the first A-loop Tyr1278 for kinase activity and NPM-ALK transforming potential. A single amino acid difference in the ALK substrate peptide binding P-1 site (where the P-site is the phosphoacceptor site) was identified that, in conjunction with A-loop sequence variation including the RAS (Arg-Ala-Ser)-motif, rationalizes the difference in the A-loop tyrosine autophosphorylation preference between ALK and IGF1RK/IRK. Enzymatic analysis of recombinant R1275Q and F1174L ALK mutant catalytic domains confirms the enhanced activity and transforming potential of these mutants. The transforming ability of the full-length ALK mutants in soft agar colony growth assays corroborates these findings. The availability of a three-dimensional structure for ALK will facilitate future structure-function and rational drug design efforts targeting this receptor tyrosine kinase. PubMed: 20632993DOI: 10.1042/BJ20100609 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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