PDBsum entry 4xey

Transferase/transferase inhibitor

PDB id: 4xey

Contents

Protein chains

359 a.a.

269 a.a.

Ligands

1N1 ×2

PDB id:

4xey

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of an sh2-kinase domain construct of c-abl tyrosine kinase

Structure:

Tyrosine-protein kinase abl1. Chain: b, a. Fragment: unp residues 119-515. Synonym: abelson murine leukemia viral oncogene homolog 1,abelson tyrosine-protein kinase 1,proto-oncogenE C-abl,p150. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: abl1, abl, jtk7. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.89Å R-factor: 0.232 R-free: 0.259

Authors:

S.Lorenz,P.Deng,J.Kuriyan

Key ref:

S.Lorenz et al. (2015). Crystal structure of an SH2-kinase construct of c-Abl and effect of the SH2 domain on kinase activity. Biochem J, 468, 283-291. PubMed id: 25779001 DOI: 10.1042/BJ20141492

Date:

25-Dec-14 Release date: 01-Apr-15

Protein chain

P00519  (ABL1_HUMAN) -  Tyrosine-protein kinase ABL1 from Homo sapiens

Seq: 1130 a.a.

Struc: 359 a.a.

Protein chain

P00519  (ABL1_HUMAN) -  Tyrosine-protein kinase ABL1 from Homo sapiens

Seq: 1130 a.a.

Struc: 269 a.a.

Enzyme reactions

• Enzyme class: Chains B, A: 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: 10.1042/BJ20141492

Biochem J 468:283-291 (2015)

PubMed id: 25779001

Crystal structure of an SH2-kinase construct of c-Abl and effect of the SH2 domain on kinase activity.

S.Lorenz, P.Deng, O.Hantschel, G.Superti-Furga, J.Kuriyan.

ABSTRACT

Constitutive activation of the non-receptor tyrosine kinase c-Abl (cellular Abelson tyrosine protein kinase 1, Abl1) in the Bcr (breakpoint cluster region)-Abl1 fusion oncoprotein is the molecular cause of chronic myeloid leukaemia (CML). Recent studies have indicated that an interaction between the SH2 (Src-homology 2) domain and the N-lobe (N-terminal lobe) of the c-Abl kinase domain (KD) has a critical role in leukaemogenesis [Grebien et al. (2011) Cell 147, 306-319; Sherbenou et al. (2010) Blood 116, 3278-3285]. To dissect the structural basis of this phenomenon, we studied c-Abl constructs comprising the SH2 and KDs in vitro. We present a crystal structure of an SH2-KD construct bound to dasatinib, which contains the relevant interface between the SH2 domain and the N-lobe of the KD. We show that the presence of the SH2 domain enhances kinase activity moderately and that this effect depends on contacts in the SH2/N-lobe interface and is abrogated by specific mutations. Consistently, formation of the interface decreases slightly the association rate of imatinib with the KD. That the effects are small compared with the dramatic in vivo consequences suggests an important function of the SH2-N-lobe interaction might be to help disassemble the auto-inhibited conformation of c-Abl and promote processive phosphorylation, rather than substantially stimulate kinase activity.