3KCF

Crystal structure of TGFbRI complexed with a pyrazolone inhibitor

Summary for 3KCF

• Entry DOI: 10.2210/pdb3kcf/pdb
• Descriptor: TGF-beta receptor type-1, 4-[3-(methoxymethyl)phenyl]-1,2-dimethyl-5-quinoxalin-6-yl-1,2-dihydro-3H-pyrazol-3-one, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: kinase, tgfbetari, structure-based drug design, protein-inhibitor complex, aortic aneurysm, atp-binding, craniosynostosis, disease mutation, disulfide bond, glycoprotein, magnesium, manganese, membrane, metal-binding, nucleotide-binding, phosphoprotein, polymorphism, receptor, serine/threonine-protein kinase, transferase, transmembrane
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P36897
• Total number of polymer chains: 5
• Total formula weight: 197639.87

Authors

Boriack-Sjodin, P.A. (deposition date: 2009-10-21, release date: 2009-12-22, Last modification date: 2024-04-03)

Primary citation

Guckian, K.,Carter, M.B.,Lin, E.Y.,Choi, M.,Sun, L.,Boriack-Sjodin, P.A.,Chuaqui, C.,Lane, B.,Cheung, K.,Ling, L.,Lee, W.C.
Pyrazolone based TGFbetaR1 kinase inhibitors.
Bioorg.Med.Chem.Lett., 20:326-329, 2010

PubMed Abstract: Interruption of TGFbeta signaling through inhibition of the TGFbetaR1 kinase domain may prove to have beneficial effect in both fibrotic and oncological diseases. Herein we describe the SAR of a novel series of TGFbetaR1 kinase inhibitors containing a pyrazolone core. Most TGFbetaR1 kinase inhibitors described to date contain a core five-membered ring bearing N as H-bond acceptor. Described herein is a novel strategy to replace the core structure with pyrazolone ring, in which the carbonyl group is designed as an H-bond acceptor to interact with catalytic Lys 232.

PubMed: 19914068
DOI: 10.1016/j.bmcl.2009.10.108

Experimental method

X-RAY DIFFRACTION (2.8 Å)