PDBsum entry 4qt1

Transferase/transferase inhibitor

PDB id: 4qt1

Contents

Protein chain

277 a.a.

Ligands

3C9

Waters ×82

PDB id:

4qt1

Name:

Transferase/transferase inhibitor

Title:

Jak3 kinase domain in complex with 1-[(3s)-1-isobutylsulfonyl-3- piperidyl]-3-(5h-pyrrolo[2,3-b]pyrazin-2-yl)urea

Structure:

Tyrosine-protein kinase jak3. Chain: a. Fragment: residues 811-1124, protein kinase domain. Synonym: janus kinase 3, jak-3, leukocyte janus kinase, l-jak. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: jak3. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.40Å R-factor: 0.210 R-free: 0.273

Authors:

A.Kuglstatter,A.Shao

Key ref:

J.de Vicente et al. (2014). Scaffold hopping towards potent and selective JAK3 inhibitors: discovery of novel C-5 substituted pyrrolopyrazines. Bioorg Med Chem Lett, 24, 4969-4975. PubMed id: 25262541 DOI: 10.1016/j.bmcl.2014.09.031

Date:

07-Jul-14 Release date: 27-May-15

Protein chain

P52333  (JAK3_HUMAN) -  Tyrosine-protein kinase JAK3 from Homo sapiens

Seq: 1124 a.a.

Struc: 277 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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

DOI no: 10.1016/j.bmcl.2014.09.031

Bioorg Med Chem Lett 24:4969-4975 (2014)

PubMed id: 25262541

Scaffold hopping towards potent and selective JAK3 inhibitors: discovery of novel C-5 substituted pyrrolopyrazines.

J.de Vicente, R.Lemoine, M.Bartlett, J.C.Hermann, M.Hekmat-Nejad, R.Henningsen, S.Jin, A.Kuglstatter, H.Li, A.J.Lovey, J.Menke, L.Niu, V.Patel, A.Petersen, L.Setti, A.Shao, P.Tivitmahaisoon, M.D.Vu, M.Soth.

ABSTRACT

The discovery of a novel series of pyrrolopyrazines as JAK inhibitors with comparable enzyme and cellular activity to tofacitinib is described. The series was identified using a scaffold hopping approach aided by structure based drug design using principles of intramolecular hydrogen bonding for conformational restriction and targeting specific pockets for modulating kinase activity.