4OKP: Crystal Structure Of Ampc Beta-lactamase In Complex With The Product Form Of 7-amino-desacetoxycephalosporanic Acid

Predicting substrates for enzymes of unknown function is a major postgenomic challenge. Substrate discovery, like inhibitor discovery, is constrained by our ability to explore chemotypes; it would be expanded by orders of magnitude if reactive sites could be probed with fragments rather than fully elaborated substrates, as is done for inhibitor discovery. To explore the feasibility of this approach, substrates of six enzymes from three different superfamilies were deconstructed into 41 overlapping fragments that were tested for activity or binding. Surprisingly, even those fragments containing the key reactive group had little activity, and most fragments did not bind measurably, until they captured most of the substrate features. Removing a single atom from a recognized substrate could often reduce catalytic recognition by 6 log-orders. To explore recognition at atomic resolution, the structures of three fragment complexes of the beta-lactamase substrate cephalothin were determined by X-ray crystallography. Substrate discovery may be difficult to reduce to the fragment level, with implications for function discovery and for the tolerance of enzymes to metabolite promiscuity. Pragmatically, this study supports the development of libraries of fully elaborated metabolites as probes for enzyme function, which currently do not exist.
PDB ID: 4OKPDownload
MMDB ID: 120327
PDB Deposition Date: 2014/1/22
Updated in MMDB: 2014/06
Experimental Method:
x-ray diffraction
Resolution: 1.37  Å
Source Organism:
Similar Structures:
Biological Unit for 4OKP: monomeric; determined by author and by software (PISA)
Molecular Components in 4OKP
Label Count Molecule
Protein (1 molecule)
Beta-lactamase(Gene symbol: ampC)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB