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Title: X-Ray Crystal Structure of Bone Marrow Kinase in the X Chromosome: A Tec Family Kinase

Abstract

Bone marrow kinase in the X chromosome, a member of the Tec family of tyrosine kinases, plays a role in both monocyte/macrophage trafficking as well as cytokine secretion. Although the structures of Tec family kinases Bruton's tyrosine kinase and IL-2-inducible T-cell kinase are known, the crystal structures of other Tec family kinases have remained elusive. We report the X-ray crystal structures of bone marrow kinase in the X chromosome in complex with dasatinib at 2.4 {angstrom} resolution and PP2 at 1.9 {angstrom} resolution. The bone marrow kinase in the X chromosome structures reveal a typical kinase protein fold; with well-ordered protein conformation that includes an open/extended activation loop and a stabilized DFG-motif rendering the kinase in an inactive conformation. Dasatinib and PP2 bind to bone marrow kinase in the X chromosome in the ATP binding pocket and display similar binding modes to that observed in other Tec and Src protein kinases. The bone marrow kinase in the X chromosome structures identify conformational elements of the DFG-motif that could potentially be utilized to design potent and/or selective bone marrow kinase in the X chromosome inhibitors.

Authors:
; ; ; ; ; ; ; ;  [1]
  1. (BMS)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1043725
Resource Type:
Journal Article
Journal Name:
Chemical Biology and Drug Design
Additional Journal Information:
Journal Volume: 78; Journal Issue: 5; Journal ID: ISSN 1747-0227
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; BONE MARROW; CRYSTAL STRUCTURE; CRYSTALLOGRAPHY; DESIGN; LYMPHOKINES; PHOSPHOTRANSFERASES; PROTEINS; RESOLUTION; SECRETION; TYROSINE; X CHROMOSOME

Citation Formats

Muckelbauer, Jodi, Sack, John S., Ahmed, Nazia, Burke, James, Chang, ChiehYing Y., Gao, Mian, Tino, Joseph, Xie, Dianlin, and Tebben, Andrew J. X-Ray Crystal Structure of Bone Marrow Kinase in the X Chromosome: A Tec Family Kinase. United States: N. p., 2012. Web. doi:10.1111/j.1747-0285.2011.01230.x.
Muckelbauer, Jodi, Sack, John S., Ahmed, Nazia, Burke, James, Chang, ChiehYing Y., Gao, Mian, Tino, Joseph, Xie, Dianlin, & Tebben, Andrew J. X-Ray Crystal Structure of Bone Marrow Kinase in the X Chromosome: A Tec Family Kinase. United States. doi:10.1111/j.1747-0285.2011.01230.x.
Muckelbauer, Jodi, Sack, John S., Ahmed, Nazia, Burke, James, Chang, ChiehYing Y., Gao, Mian, Tino, Joseph, Xie, Dianlin, and Tebben, Andrew J. Wed . "X-Ray Crystal Structure of Bone Marrow Kinase in the X Chromosome: A Tec Family Kinase". United States. doi:10.1111/j.1747-0285.2011.01230.x.
@article{osti_1043725,
title = {X-Ray Crystal Structure of Bone Marrow Kinase in the X Chromosome: A Tec Family Kinase},
author = {Muckelbauer, Jodi and Sack, John S. and Ahmed, Nazia and Burke, James and Chang, ChiehYing Y. and Gao, Mian and Tino, Joseph and Xie, Dianlin and Tebben, Andrew J.},
abstractNote = {Bone marrow kinase in the X chromosome, a member of the Tec family of tyrosine kinases, plays a role in both monocyte/macrophage trafficking as well as cytokine secretion. Although the structures of Tec family kinases Bruton's tyrosine kinase and IL-2-inducible T-cell kinase are known, the crystal structures of other Tec family kinases have remained elusive. We report the X-ray crystal structures of bone marrow kinase in the X chromosome in complex with dasatinib at 2.4 {angstrom} resolution and PP2 at 1.9 {angstrom} resolution. The bone marrow kinase in the X chromosome structures reveal a typical kinase protein fold; with well-ordered protein conformation that includes an open/extended activation loop and a stabilized DFG-motif rendering the kinase in an inactive conformation. Dasatinib and PP2 bind to bone marrow kinase in the X chromosome in the ATP binding pocket and display similar binding modes to that observed in other Tec and Src protein kinases. The bone marrow kinase in the X chromosome structures identify conformational elements of the DFG-motif that could potentially be utilized to design potent and/or selective bone marrow kinase in the X chromosome inhibitors.},
doi = {10.1111/j.1747-0285.2011.01230.x},
journal = {Chemical Biology and Drug Design},
issn = {1747-0227},
number = 5,
volume = 78,
place = {United States},
year = {2012},
month = {6}
}