4NCT

Human DYRK1A in complex with PKC412

Summary for 4NCT

• Entry DOI: 10.2210/pdb4nct/pdb
• Descriptor: Dual specificity tyrosine-phosphorylation-regulated kinase 1A, PKC412, ... (4 entities in total)
• Functional Keywords: protein kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus : Q13627 Q13627
• Total number of polymer chains: 4
• Total formula weight: 172978.49

Authors

Alexeeva, M.O.,Rothweiler, U. (deposition date: 2013-10-25, release date: 2015-04-01, Last modification date: 2024-11-20)

Primary citation

Alexeeva, M.,Aberg, E.,Engh, R.A.,Rothweiler, U.
The structure of a dual-specificity tyrosine phosphorylation-regulated kinase 1A-PKC412 complex reveals disulfide-bridge formation with the anomalous catalytic loop HRD(HCD) cysteine.
Acta Crystallogr.,Sect.D, 71:1207-1215, 2015

PubMed Abstract: Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a protein kinase associated with neuronal development and brain physiology. The DYRK kinases are very unusual with respect to the sequence of the catalytic loop, in which the otherwise highly conserved arginine of the HRD motif is replaced by a cysteine. This replacement, along with the proximity of a potential disulfide-bridge partner from the activation segment, implies a potential for redox control of DYRK family activities. Here, the crystal structure of DYRK1A bound to PKC412 is reported, showing the formation of the disulfide bridge and associated conformational changes of the activation loop. The DYRK kinases represent emerging drug targets for several neurological diseases as well as cancer. The observation of distinct activation states may impact strategies for drug targeting. In addition, the characterization of PKC412 binding offers new insights for DYRK inhibitor discovery.

PubMed: 25945585
DOI: 10.1107/S1399004715005106

Experimental method

X-RAY DIFFRACTION (2.597 Å)