PDBsum entry 4k6z

Transferase/transferase inhibitor

PDB id

4k6z

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Contents

			Protein chain

					281 a.a.

			Ligands

					1Q3

			Waters ×28

PDB id:

4k6z

Links

Name:

Transferase/transferase inhibitor

Title:

The jak1 kinase domain in complex with compound 37

Structure:

Tyrosine-protein kinase jak1. Chain: a. Fragment: jak1 kinase domain, unp residues 854-1154. Synonym: janus kinase 1, jak-1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: jak1, jak1a, jak1b. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.73Å

R-factor:

0.244

R-free:

0.297

Authors:

R.Fong,P.J.Lupardus

Key ref:

S.Labadie et al. (2013). Design and evaluation of novel 8-oxo-pyridopyrimidine Jak1/2 inhibitors. Bioorg Med Chem Lett, 23, 5923-5930. PubMed id: 24042009 DOI: 10.1016/j.bmcl.2013.08.082

Date:

16-Apr-13

Release date:

02-Oct-13

PROCHECK

	Headers

	References

Protein chain

P23458 (JAK1_HUMAN) - Tyrosine-protein kinase JAK1 from Homo sapiens

Seq: Struc:

Seq: Struc:

Seq: Struc:					1154 a.a. 281 a.a.

Key:

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.2.7.10.2 - non-specific protein-tyrosine kinase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

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

DOI no: 10.1016/j.bmcl.2013.08.082	Bioorg Med Chem Lett 23:5923-5930 (2013)
PubMed id: 24042009

Design and evaluation of novel 8-oxo-pyridopyrimidine Jak1/2 inhibitors.
S.Labadie, K.Barrett, W.S.Blair, C.Chang, G.Deshmukh, C.Eigenbrot, P.Gibbons, A.Johnson, J.R.Kenny, P.B.Kohli, M.Liimatta, P.J.Lupardus, S.Shia, M.Steffek, S.Ubhayakar, A.van Abbema, M.Zak.

ABSTRACT

A highly ligand efficient, novel 8-oxo-pyridopyrimidine containing inhibitor of Jak1 and Jak2 isoforms with a pyridone moiety as the hinge-binding motif was discovered. Structure-based design strategies were applied to significantly improve enzyme potency and the polarity of the molecule was adjusted to gain cellular activity. The crystal structures of two representative inhibitors bound to Jak1 were obtained to enable SAR exploration.