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 #
5P41RR001633-20
Application #
6618411
Study Section
Project Start
2002-09-01
Project End
2003-08-31
Budget Start
Budget End
Support Year
20
Fiscal Year
2002
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
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
Uchida, Takeshi; He, Qin; Ralston, Corie Y et al. (2002) Linkage of monovalent and divalent ion binding in the folding of the P4-P6 domain of the Tetrahymena ribozyme. Biochemistry 41:5799-806
Tang, Qun; Carrington, Paul E; Horng, Yih-Chern et al. (2002) X-ray absorption and resonance Raman studies of methyl-coenzyme M reductase indicating that ligand exchange and macrocycle reduction accompany reductive activation. J Am Chem Soc 124:13242-56
Guan, Jing-Qu; Vorobiev, Sergeui; Almo, Steven C et al. (2002) Mapping the G-actin binding surface of cofilin using synchrotron protein footprinting. Biochemistry 41:5765-75

Showing the most recent 10 out of 68 publications