PDBsum entry 3fup

Transferase

PDB id: 3fup

Contents

Protein chain

286 a.a. *

Ligands

MI1 ×2

Waters ×135

* Residue conservation analysis

PDB id:

3fup

Name:

Transferase

Title:

Crystal structures of jak1 and jak2 inhibitor complexes

Structure:

Tyrosine-protein kinase jak2. Chain: a, b. Fragment: catalytic domain. Synonym: janus kinase 2, jak-2. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: jak2, jak2 (amino acids 843 - 1132). Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.40Å R-factor: 0.182 R-free: 0.250

Authors:

N.K.Williams,R.S.Bamert,O.Patel,E.Fantino,J.Rossjohn,I.S.Lucet

Key ref:

N.K.Williams et al. (2009). Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains. J Mol Biol, 387, 219-232. PubMed id: 19361440 DOI: 10.1016/j.jmb.2009.01.041

Date:

14-Jan-09 Release date: 10-Feb-09

Protein chains

O60674  (JAK2_HUMAN) -  Tyrosine-protein kinase JAK2 from Homo sapiens

Seq: 1132 a.a.

Struc: 286 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.jmb.2009.01.041

J Mol Biol 387:219-232 (2009)

PubMed id: 19361440

Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains.

N.K.Williams, R.S.Bamert, O.Patel, C.Wang, P.M.Walden, A.F.Wilks, E.Fantino, J.Rossjohn, I.S.Lucet.

ABSTRACT

The Janus kinases (JAKs) are a pivotal family of protein tyrosine kinases (PTKs) that play prominent roles in numerous cytokine signaling pathways, with aberrant JAK activity associated with a variety of hematopoietic malignancies, cardiovascular diseases and immune-related disorders. Whereas the structures of the JAK2 and JAK3 PTK domains have been determined, the structure of the JAK1 PTK domain is unknown. Here, we report the high-resolution crystal structures of the "active form" of the JAK1 PTK domain in complex with two JAK inhibitors, a tetracyclic pyridone 2-t-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-one (CMP6) and (3R,4R)-3-[4-methyl-3-[N-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile (CP-690,550), and compare them with the corresponding JAK2 PTK inhibitor complexes. Both inhibitors bound in a similar manner to JAK1, namely buried deep within a constricted ATP-binding site, thereby providing a basis for the potent inhibition of JAK1. As expected, the mode of inhibitor binding in JAK1 was very similar to that observed in JAK2, highlighting the challenges in developing JAK-specific inhibitors that target the ATP-binding site. Nevertheless, differences surrounding the JAK1 and JAK2 ATP-binding sites were apparent, thereby providing a platform for the rational design of JAK2- and JAK1-specific inhibitors.

Selected figure(s)

Figure 4.
Fig. 4. Modes of inhibitor binding to the JAK1 and JAK2 kinase domains. (a) Interaction between CMP6 and JAK1 PTK. (b) Interaction between CP-690,550 and JAK1 PTK. (c) Interaction between CP-690,550 and JAK2 PTK. The left panel shows the side chains of residues that interact with the inhibitor as well as the main-chain atoms and water molecules participating in hydrogen bonds. The right panel shows a corresponding view of the inhibitor in a ball-and-stick representation and covered with the simulated annealing F[o] − F[c] electron density omit map contoured at 3σ. (d) Chemical structures of CMP6 (left) and CP-690,550 (right). Functional group names are indicated, and atoms are labeled according to the Protein Data Bank structure files. Carbon, nitrogen, oxygen and fluorene atoms are shown in yellow, blue, red and gray, respectively.

Figure 6.
Fig. 6. Comparison of the active-site regions of JAK1 and JAK2. Superposition of JAK1 PTK (green) and JAK2 PTK (cyan) in complex with CMP6 (a) and CP-690,550 (b). Unique residues within 5 Å of the inhibitor are shown.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2009, 387, 219-232) copyright 2009.

Figures were selected by the author.