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Three-dimensional structure of the Hck SH2 domain in solution
W Zhang1, T E Smithgall, W H Gmeiner
1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha 68198-6805, USA.
Journal of Biomolecular NMR
|December 9, 1997
Summary
We determined the structure of the hematopoietic cellular kinase (Hck) SH2 domain using NMR spectroscopy. This provides insights into Hck regulation in normal and pathological conditions, like HIV infection and leukemia.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Medicine
Background:
- Hematopoietic cellular kinase (Hck) is a Src family tyrosine kinase.
- Hck is predominantly expressed in myeloid cells.
- Hck activation is implicated in HIV infection and chronic myelogenous leukemia (CML).
Purpose of the Study:
- To elucidate the structural basis of Hck regulation.
- To understand Hck function in normal and pathological states.
Main Methods:
- Solution structure determination of the uncomplexed Hck SH2 domain using Nuclear Magnetic Resonance (NMR) spectroscopy.
- Novel method for converting Nuclear Overhauser Effect (NOE) intensities to distance restraints using intraresidue HN-Hα distances.
- Structure generation using simulated annealing with the program DYANA.
Main Results:
- A total of 1757 experimental restraints were obtained, including distance and torsion angle restraints.
- 20 structures were generated, showing high precision with low root-mean-square deviation (RMSD) values.
- The structure of the Hck SH2 domain was solved with atomic-level detail.
Conclusions:
- The determined Hck SH2 domain structure provides a foundation for understanding its regulatory mechanisms.
- This structural information can inform therapeutic strategies targeting Hck in diseases like HIV and CML.