PDBsum entry 4fz6

Transferase/transferase inhibitor

PDB id: 4fz6

Contents

Protein chain

266 a.a.

Ligands

0VG

Waters ×111

PDB id:

4fz6

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of spleen tyrosine kinase complexed with [6-((s)-2- methyl-pyrrolidin-1-yl)-pyridin-2-yl]-(6-phenyl-imidazo[1,2- b]pyridazin-8-yl)-amine

Structure:

Tyrosine-protein kinase syk. Chain: a. Fragment: residues 356-635, protein kinase domain. Synonym: spleen tyrosine kinase, p72-syk. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: syk. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

1.85Å R-factor: 0.230 R-free: 0.253

Authors:

A.Kuglstatter,M.Slade

Key ref:

M.C.Lucas et al. (2012). Rational design of highly selective spleen tyrosine kinase inhibitors. J Med Chem, 55, 10414-10423. PubMed id: 23151054

Date:

06-Jul-12 Release date: 30-Jan-13

Protein chain

P43405  (KSYK_HUMAN) -  Tyrosine-protein kinase SYK from Homo sapiens

Seq: 635 a.a.

Struc: 266 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

J Med Chem 55:10414-10423 (2012)

PubMed id: 23151054

Rational design of highly selective spleen tyrosine kinase inhibitors.

M.C.Lucas, D.M.Goldstein, J.C.Hermann, A.Kuglstatter, W.Liu, K.C.Luk, F.Padilla, M.Slade, A.G.Villaseñor, J.Wanner, W.Xie, X.Zhang, C.Liao.

ABSTRACT

A novel approach to design selective spleen tyrosine kinase (Syk) inhibitors is described. Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of autoimmune diseases such as asthma, rheumatoid arthritis, and SLE. Fostamatinib, a Syk inhibitor that successfully completed phase II clinical trials, also exhibits some undesirable side effects. More selective Syk inhibitors could offer safer, alternative treatments. Through a systematic evaluation of the kinome, we identified Pro455 and Asn457 in the Syk ATP binding site as a rare combination among sequence aligned kinases and hypothesized that optimizing the interaction between them and a Syk inhibitor molecule would impart high selectivity for Syk over other kinases. We report the structure-guided identification of three series of selective spleen tyrosine kinase inhibitors that support our hypothesis and offer useful guidance to other researchers in the field.