PDBsum entry 3byu

Transferase

PDB id: 3byu

Contents

Protein chain

256 a.a. *

Ligands

AM6

Waters ×126

* Residue conservation analysis

PDB id:

3byu

Name:

Transferase

Title:

Co-crystal structure of lck and aminopyrimidine reverse amide 23

Structure:

Proto-oncogene tyrosine-protein kinase lck. Chain: a. Fragment: kinase domain. Synonym: p56-lck, lymphocyte cell-specific protein-tyrosine kinase, lsk, t cell-specific protein-tyrosine kinase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: lck. Expressed in: baculovirus. Expression_system_cell_line: insect cell

Resolution:

2.30Å R-factor: 0.232 R-free: 0.278

Authors:

X.Huang

Key ref:

E.F.DiMauro et al. (2008). Structure-guided design of aminopyrimidine amides as potent, selective inhibitors of lymphocyte specific kinase: synthesis, structure-activity relationships, and inhibition of in vivo T cell activation. J Med Chem, 51, 1681-1694. PubMed id: 18321037

Date:

16-Jan-08 Release date: 16-Sep-08

Protein chain

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

Seq: 509 a.a.

Struc: 256 a.a.

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

J Med Chem 51:1681-1694 (2008)

PubMed id: 18321037

Structure-guided design of aminopyrimidine amides as potent, selective inhibitors of lymphocyte specific kinase: synthesis, structure-activity relationships, and inhibition of in vivo T cell activation.

E.F.DiMauro, J.Newcomb, J.J.Nunes, J.E.Bemis, C.Boucher, L.Chai, S.C.Chaffee, H.L.Deak, L.F.Epstein, T.Faust, P.Gallant, A.Gore, Y.Gu, B.Henkle, F.Hsieh, X.Huang, J.L.Kim, J.H.Lee, M.W.Martin, D.C.McGowan, D.Metz, D.Mohn, K.A.Morgenstern, A.Oliveira-dos-Santos, V.F.Patel, D.Powers, P.E.Rose, S.Schneider, S.A.Tomlinson, Y.Y.Tudor, S.M.Turci, A.A.Welcher, H.Zhao, L.Zhu, X.Zhu.

ABSTRACT

The lymphocyte-specific kinase (Lck), a member of the Src family of cytoplasmic tyrosine kinases, is expressed in T cells and natural killer (NK) cells. Genetic evidence, including knockout mice and human mutations, demonstrates that Lck kinase activity is critical for normal T cell development, activation, and signaling. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. With the aid of X-ray structure-based analysis, aminopyrimidine amides 2 and 3 were designed from aminoquinazolines 1, which had previously been demonstrated to exhibit potent inhibition of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminopyrimidine amides 3 possessing improved cellular potency and selectivity profiles relative to their aminoquinazoline predecessors 1. Orally bioavailable compound 13b inhibited the anti-CD3-induced production of interleukin-2 (IL-2) in mice in a dose-dependent manner (ED 50 = 9.4 mg/kg).