PDBsum entry 4lgg

Transferase/transferase inhibitor

PDB id: 4lgg

Contents

Protein chains

241 a.a.

Ligands

VGG ×2

Waters ×46

PDB id:

4lgg

Name:

Transferase/transferase inhibitor

Title:

Structure of 3mb-pp1 bound to analog-sensitive src kinase

Structure:

Proto-oncogene tyrosine-protein kinase src. Chain: a, b. Fragment: kinase domain (unp residues 264-533). Synonym: proto-oncogenE C-src, pp60c-src, p60-src. Engineered: yes. Mutation: yes

Source:

Gallus gallus. Bantam,chickens. Organism_taxid: 9031. Gene: src. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.41Å R-factor: 0.238 R-free: 0.285

Authors:

M.S.Lopez,A.C.Dar,K.M.Shokat

Key ref:

C.Zhang et al. (2013). Structure-guided inhibitor design expands the scope of analog-sensitive kinase technology. Acs Chem Biol, 8, 1931-1938. PubMed id: 23841803 DOI: 10.1021/cb400376p

Date:

27-Jun-13 Release date: 07-Aug-13

Protein chains

P00523  (SRC_CHICK) -  Proto-oncogene tyrosine-protein kinase Src from Gallus gallus

Seq: 533 a.a.

Struc: 241 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: 10.1021/cb400376p

Acs Chem Biol 8:1931-1938 (2013)

PubMed id: 23841803

Structure-guided inhibitor design expands the scope of analog-sensitive kinase technology.

C.Zhang, M.S.Lopez, A.C.Dar, E.Ladow, S.Finkbeiner, C.H.Yun, M.J.Eck, K.M.Shokat.

ABSTRACT

Engineered analog-sensitive (AS) protein kinases have emerged as powerful tools for dissecting phospho-signaling pathways, for elucidating the cellular function of individual kinases, and for deciphering unanticipated effects of clinical therapeutics. A crucial and necessary feature of this technology is a bioorthogonal small molecule that is innocuous toward native cellular systems but potently inhibits the engineered kinase. In order to generalize this method, we sought a molecule capable of targeting divergent AS-kinases. Here we employ X-ray crystallography and medicinal chemistry to unravel the mechanism of current inhibitors and use these insights to design the most potent, selective, and general AS-kinase inhibitors reported to date. We use large-scale kinase inhibitor profiling to characterize the selectivity of these molecules as well as examine the consequences of potential off-target effects in chemical genetic experiments. The molecules reported here will serve as powerful tools in efforts to extend AS-kinase technology to the entire kinome and the principles discovered may help in the design of other engineered enzyme/ligand pairs.