X-Ray Structure of A Penicillin Receptor

Knox, James Russell

Abstract

We will use x-ray crystallographic methods to determine the molecular structure of a penicillin receptor, the D-alanyl-carboxypeptidase-transpeptidase from streptomyces R61. Examination of its interaction with a series of Beta-lactam antibiotics will allow us to correlate their relative activity with their binding geometry to the receptor. Coupled with our concurrent X-ray analysis of a penicillin-destroying Beta-lactamase enzyme, this study could conceivably lead to new Beta-lactams which are not only more effective inhibitors of bacterial cell wall receptors, but also more resistant to hydrolysis by the medically-troublesome Beta-lactamases. Preliminary crystallographic data have been reported (Knox et al. J. Molec. Biol. 127, 217-218 (1979)).

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of General Medical Sciences (NIGMS)
• Type: Research Project (R01)
• Project #: 5R01GM037742-08
• Application #: 3293371
• Study Section: Biophysics and Biophysical Chemistry B Study Section (BBCB)
• Project Start: 1986-04-01
• Project End: 1989-03-31
• Budget Start: 1987-04-01
• Budget End: 1988-03-31
• Support Year: 8
• Fiscal Year: 1987

Institution

• Name: University of Connecticut
• Type: Graduate Schools
• City: Storrs-Mansfield
• State: CT
• Country: United States
• Zip Code: 06269

Publications

Kuzin, A P; Liu, H; Kelly, J A et al. (1995) Binding of cephalothin and cefotaxime to D-ala-D-ala-peptidase reveals a functional basis of a natural mutation in a low-affinity penicillin-binding protein and in extended-spectrum beta-lactamases. Biochemistry 34:9532-40

Moews, P C; Knox, J R; Dideberg, O et al. (1990) Beta-lactamase of Bacillus licheniformis 749/C at 2 A resolution. Proteins 7:156-71

Kelly, J A; Knox, J R; Zhao, H et al. (1989) Crystallographic mapping of beta-lactams bound to a D-alanyl-D-alanine peptidase target enzyme. J Mol Biol 209:281-95

Kelly, J A; Knox, J R; Zhao, H (1989) Studying enzyme-beta-lactam interactions using X-ray diffraction. J Mol Graph 7:87-92

Murthy, N S; Braswell, E H; Knox, J R (1988) The association behavior of beta-lactamases in polyethylene glycol solution. Biopolymers 27:865-81

Kelly, J A; Knox, J R; Moews, P C et al. (1988) Using X-ray diffraction results and computer graphics to design beta-lactams. Kansenshogaku Zasshi 62 Suppl:182-91

Joris, B; Ghuysen, J M; Dive, G et al. (1988) The active-site-serine penicillin-recognizing enzymes as members of the Streptomyces R61 DD-peptidase family. Biochem J 250:313-24

Frank, H A; Taremi, S S; Knox, J R (1987) Crystallization and preliminary X-ray and optical spectroscopic characterization of the photochemical reaction center from Rhodobacter sphaeroides strain 2.4.1. J Mol Biol 198:139-41