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

doi:10.1111/j.1747-0285.2011.01230.x

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

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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:

Muckelbauer, Jodi; Sack, John S.; Ahmed, Nazia; Burke, James; Chang, ChiehYing Y.; Gao, Mian; Tino, Joseph; Xie, Dianlin; Tebben, Andrew J. ^[1]

(BMS)

Publication Date:: 2012-06-27

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.

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                    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.

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                    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.

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@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}

}

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DOI: 10.1111/j.1747-0285.2011.01230.x

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