Abstract

Purine nuceloside phosphorylase (PNP) catalyzes the phosphorolysis of purine nucleosides to yield free purines and ?-1-ribose phosphate. A genetic defect in humans that results in the lack of PNP, results in a complete loss of T-cells, but no other effects. Thus PNP is an excellent target for the therapy of a number of T-cell specific pathologies including T-cell lymphomas and graft rejection. We have recently collected data to better than 2.0E on a complex between calf spleen PNP and a 20 pM transition state-inhibitor. Refinement is underway and currently reveals several of the strategies used by this enzyme to stabilize the transition state, which includes a conformational rearrangement. This structure represents one of the highest affinity enzyme-ligand complexes solved to date and will form the basis for future inhibitor development and mechanistic studies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001633-18
Application #
6345144
Study Section
Project Start
2000-09-01
Project End
2001-08-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
18
Fiscal Year
2000
Total Cost
Indirect Cost

  Institution

Name
Albert Einstein College of Medicine
Department
Type
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461

  Publications

Vongsvivut, Jitraporn; Fernandez, Jason; Ekgasit, Sanong et al. (2004) Characterization of supported cylinder-planar germanium waveguide sensors with synchrotron infrared radiation. Appl Spectrosc 58:143-51
Masip, Lluis; Pan, Jonathan L; Haldar, Suranjana et al. (2004) An engineered pathway for the formation of protein disulfide bonds. Science 303:1185-9
Huang, Raymond Y; Miller, Lisa M; Carlson, Cathy S et al. (2003) In situ chemistry of osteoporosis revealed by synchrotron infrared microspectroscopy. Bone 33:514-21
Rashidzadeh, Hassan; Khrapunov, Sergei; Chance, Mark R et al. (2003) Solution structure and interdomain interactions of the Saccharomyces cerevisiae ""TATA binding protein"" (TBP) probed by radiolytic protein footprinting. Biochemistry 42:3655-65
Uchida, Takeshi; Takamoto, Keiji; He, Qin et al. (2003) Multiple monovalent ion-dependent pathways for the folding of the L-21 Tetrahymena thermophila ribozyme. J Mol Biol 328:463-78
Taylor, Colleen M; Watton, Stephen P; Bryngelson, Peter A et al. (2003) Inner-sphere complexation of cobalt(II) 2,9-dimethyl-1,10-phenanthroline ([Co(neo)]2+) with commercial and sol-gel derived silica gel surfaces. Inorg Chem 42:312-20
Dewan, John C; Feeling-Taylor, Angela; Puius, Yoram A et al. (2002) Structure of mutant human carbonmonoxyhemoglobin C (betaE6K) at 2.0 A resolution. Acta Crystallogr D Biol Crystallogr 58:2038-42
Kiselar, J G; Maleknia, S D; Sullivan, M et al. (2002) Hydroxyl radical probe of protein surfaces using synchrotron X-ray radiolysis and mass spectrometry. Int J Radiat Biol 78:101-14
Swisher, Jennifer F; Su, Linhui J; Brenowitz, Michael et al. (2002) Productive folding to the native state by a group II intron ribozyme. J Mol Biol 315:297-310
Dhavan, Gauri M; Crothers, Donald M; Chance, Mark R et al. (2002) Concerted binding and bending of DNA by Escherichia coli integration host factor. J Mol Biol 315:1027-37

Showing the most recent 10 out of 68 publications