PDBsum entry 4fk6

Transferase/transferase inhibitor

PDB id: 4fk6

Contents

Protein chain

287 a.a.

Ligands

0UJ ×2

Waters ×138

PDB id:

4fk6

Name:

Transferase/transferase inhibitor

Title:

Jak1 kinase (jh1 domain) in complex with compound 72

Structure:

Tyrosine-protein kinase jak1. Chain: a, b. Fragment: jh1 (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:

2.20Å R-factor: 0.211 R-free: 0.251

Authors:

C.Eigenbrot,M.Steffek

Key ref:

S.Labadie et al. (2012). Structure-based discovery of C-2 substituted imidazo-pyrrolopyridine JAK1 inhibitors with improved selectivity over JAK2. Bioorg Med Chem Lett, 22, 7627-7633. PubMed id: 23107482

Date:

12-Jun-12 Release date: 07-Nov-12

Protein chains

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

Seq: 1154 a.a.

Struc: 287 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

Bioorg Med Chem Lett 22:7627-7633 (2012)

PubMed id: 23107482

Structure-based discovery of C-2 substituted imidazo-pyrrolopyridine JAK1 inhibitors with improved selectivity over JAK2.

S.Labadie, P.S.Dragovich, K.Barrett, W.S.Blair, P.Bergeron, C.Chang, G.Deshmukh, C.Eigenbrot, N.Ghilardi, P.Gibbons, C.A.Hurley, A.Johnson, J.R.Kenny, P.B.Kohli, J.J.Kulagowski, M.Liimatta, P.J.Lupardus, R.Mendonca, J.M.Murray, R.Pulk, S.Shia, M.Steffek, S.Ubhayakar, M.Ultsch, A.van Abbema, S.Ward, M.Zak.

ABSTRACT

Herein we describe our successful efforts in obtaining C-2 substituted imidazo-pyrrolopyridines with improved JAK1 selectivity relative to JAK2 by targeting an amino acid residue that differs between the two isoforms (JAK1: E966; JAK2: D939). Efforts to improve cellular potency by reducing the polarity of the inhibitors are also detailed. The X-ray crystal structure of a representative inhibitor in complex with the JAK1 enzyme is also disclosed.