PDBsum entry 4c3f

Transferase

PDB id: 4c3f

Contents

Protein chain

257 a.a.

Ligands

7KW

Waters ×355

PDB id:

4c3f

Name:

Transferase

Title:

Structure of lck in complex with a compound discovered by virtual fragment linking

Structure:

Tyrosine-protein kinase lck. Chain: a. Fragment: kinase domain, residues 237-501. Synonym: leukocytE C-terminal src kinase, lsk, lymphocyte cell- specific protein-tyrosine kinase, protein yt16, proto-oncogene lck, t cell-specific protein-tyrosine kinase, p56-lck. Engineered: yes. Mutation: yes

Source:

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

Resolution:

1.72Å R-factor: 0.180 R-free: 0.220

Authors:

S.W.Cowan-Jacob,G.Rummel,W.Stark

Key ref:

A.M.Wassermann et al. (2013). Efficient search of chemical space: navigating from fragments to structurally diverse chemotypes. J Med Chem, 56, 8879-8891. PubMed id: 24117015 DOI: 10.1021/jm401309q

Date:

23-Aug-13 Release date: 23-Oct-13

Protein chain

P06239  (LCK_HUMAN) -  Tyrosine-protein kinase Lck from Homo sapiens

Seq: 509 a.a.

Struc: 257 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/jm401309q

J Med Chem 56:8879-8891 (2013)

PubMed id: 24117015

Efficient search of chemical space: navigating from fragments to structurally diverse chemotypes.

A.M.Wassermann, P.S.Kutchukian, E.Lounkine, T.Luethi, J.Hamon, M.T.Bocker, H.A.Malik, S.W.Cowan-Jacob, M.Glick.

ABSTRACT

We introduce a novel strategy to sample bioactive chemical space, which follows-up on hits from fragment campaigns without the need for a crystal structure. Our results strongly suggest that screening a few hundred or thousand fragments can substantially improve the selection of small-molecule screening subsets. By combining fragment-based screening with virtual fragment linking and HTS fingerprints, we have developed an effective strategy not only to expand from low-affinity hits to potent compounds but also to hop in chemical space to substantially novel chemotypes. In benchmark calculations, our approach accessed subsets of compounds that were substantially enriched in chemically diverse hit compounds for various activity classes. Overall, half of the hits in the screening collection were found by screening only 10% of the library. Furthermore, a prospective application led to the discovery of two structurally novel histone deacetylase 4 inhibitors.