2WO6

Human Dual-Specificity Tyrosine-Phosphorylation-Regulated Kinase 1A in complex with a consensus substrate peptide

Summary for 2WO6

• Entry DOI: 10.2210/pdb2wo6/pdb
• Related: 2VX3
• Descriptor: DUAL SPECIFICITY TYROSINE-PHOSPHORYLATION- REGULATED KINASE 1A, ARTIFICIAL CONSENSUS SEQUENCE, N-(5-{[(2S)-4-amino-2-(3-chlorophenyl)butanoyl]amino}-1H-indazol-3-yl)benzamide, ... (5 entities in total)
• Functional Keywords: transferase-peptide complex, transferase peptide complex, serine/threonine-protein atp-binding, phosphoprotein, nucleotide-binding, dyrk1, dyrk1a, kinase, nucleus, transferase, tyrosine-protein kinase, transferase/peptide
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Nucleus speckle: Q13627
• Total number of polymer chains: 3
• Total formula weight: 90820.57

Authors

Roos, A.K.,Soundararajan, M.,Elkins, J.M.,Fedorov, O.,Eswaran, J.,Phillips, C.,Pike, A.C.W.,Ugochukwu, E.,Muniz, J.R.C.,Burgess-Brown, N.,von Delft, F.,Arrowsmith, C.H.,Wikstrom, M.,Edwards, A.,Bountra, C.,Knapp, S. (deposition date: 2009-07-22, release date: 2009-08-18, Last modification date: 2023-12-20)

Primary citation

Soundararajan, M.,Roos, A.K.,Savitsky, P.,Filippakopoulos, P.,Kettenbach, A.N.,Olsen, J.V.,Gerber, S.A.,Eswaran, J.,Knapp, S.,Elkins, J.M.
Structures of Down Syndrome Kinases, Dyrks, Reveal Mechanisms of Kinase Activation and Substrate Recognition.
Structure, 21:986-, 2013

PubMed Abstract: Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinases (DYRKs) play key roles in brain development, regulation of splicing, and apoptosis, and are potential drug targets for neurodegenerative diseases and cancer. We present crystal structures of one representative member of each DYRK subfamily: DYRK1A with an ATP-mimetic inhibitor and consensus peptide, and DYRK2 including NAPA and DH (DYRK homology) box regions. The current activation model suggests that DYRKs are Ser/Thr kinases that only autophosphorylate the second tyrosine of the activation loop YxY motif during protein translation. The structures explain the roles of this tyrosine and of the DH box in DYRK activation and provide a structural model for DYRK substrate recognition. Phosphorylation of a library of naturally occurring peptides identified substrate motifs that lack proline in the P+1 position, suggesting that DYRK1A is not a strictly proline-directed kinase. Our data also show that DYRK1A wild-type and Y321F mutant retain tyrosine autophosphorylation activity.

PubMed: 23665168
DOI: 10.1016/J.STR.2013.03.012

Experimental method

X-RAY DIFFRACTION (2.5 Å)