4WUA
Crystal structure of human SRPK1 complexed to an inhibitor SRPIN340
Summary for 4WUA
| Entry DOI | 10.2210/pdb4wua/pdb |
| Descriptor | SRSF protein kinase 1, linker, SRSF protein kinase 1, N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]-4-pyridinecarboxamide, CITRIC ACID, ... (4 entities in total) |
| Functional Keywords | protein kinase, kinase-inhibitor complex, pre-mrna splicing, atp-binding, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 46180.54 |
| Authors | Hoshina, M.,Ikura, T.,Hosoya, T.,Hagiwara, M.,Ito, N. (deposition date: 2014-10-31, release date: 2015-09-16, Last modification date: 2023-11-08) |
| Primary citation | Morooka, S.,Hoshina, M.,Kii, I.,Okabe, T.,Kojima, H.,Inoue, N.,Okuno, Y.,Denawa, M.,Yoshida, S.,Fukuhara, J.,Ninomiya, K.,Ikura, T.,Furuya, T.,Nagano, T.,Noda, K.,Ishida, S.,Hosoya, T.,Ito, N.,Yoshimura, N.,Hagiwara, M. Identification of a Dual Inhibitor of SRPK1 and CK2 That Attenuates Pathological Angiogenesis of Macular Degeneration in Mice Mol.Pharmacol., 88:316-325, 2015 Cited by PubMed Abstract: Excessive angiogenesis contributes to numerous diseases, including cancer and blinding retinopathy. Antibodies against vascular endothelial growth factor (VEGF) have been approved and are widely used in clinical treatment. Our previous studies using SRPIN340, a small molecule inhibitor of SRPK1 (serine-arginine protein kinase 1), demonstrated that SRPK1 is a potential target for the development of antiangiogenic drugs. In this study, we solved the structure of SRPK1 bound to SRPIN340 by X-ray crystallography. Using pharmacophore docking models followed by in vitro kinase assays, we screened a large-scale chemical library, and thus identified a new inhibitor of SRPK1. This inhibitor, SRPIN803, prevented VEGF production more effectively than SRPIN340 owing to the dual inhibition of SRPK1 and CK2 (casein kinase 2). In a mouse model of age-related macular degeneration, topical administration of eye ointment containing SRPIN803 significantly inhibited choroidal neovascularization, suggesting a clinical potential of SRPIN803 as a topical ointment for ocular neovascularization. Thus SRPIN803 merits further investigation as a novel inhibitor of VEGF. PubMed: 25993998DOI: 10.1124/mol.114.097345 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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