3V1P: Crystal Structure Of The Mutant Q185a Of Orotidine 5'-monophosphate Decarboxylase From Methanobacterium Thermoautotrophicum Complexed With The Inhibitor Bmp

Citation:
Abstract
The binding of a ligand to orotidine 5'-monophosphate decarboxylase (OMPDC) is accompanied by a conformational change from an open, inactive conformation (E(o)) to a closed, active conformation (E(c)). As the substrate traverses the reaction coordinate to form the stabilized vinyl carbanion/carbene intermediate, interactions that destabilize the carboxylate group of the substrate and stabilize the intermediate (in the E(c).S() complex) are enforced. Focusing on the OMPDC from Methanothermobacter thermautotrophicus, we find the "remote" 5'-phosphate group of the substrate activates the enzyme 2.4 x 10(8)-fold; the activation is equivalently described by an intrinsic binding energy (IBE) of 11.4 kcal/mol. We studied residues in the activation that (1) directly contact the 5'-phosphate group, (2) participate in a hydrophobic cluster near the base of the active site loop that sequesters the bound substrate from the solvent, and (3) form hydrogen bonding interactions across the interface between the "mobile" and "fixed" half-barrel domains of the (beta/alpha)(8)-barrel structure. Our data support a model in which the IBE provided by the 5'-phosphate group is used to allow interactions both near the N-terminus of the active site loop and across the domain interface that stabilize both the E(c).S and E(c).S() complexes relative to the E(o).S complex. The conclusion that the IBE of the 5'-phosphate group provides stabilization to both the E(c).S and E(c).S() complexes, not just the E(c).S() complex, is central to understanding the structural origins of enzymatic catalysis as well as the requirements for the de novo design of enzymes that catalyze novel reactions.
PDB ID: 3V1PDownload
MMDB ID: 105155
PDB Deposition Date: 2011/12/9
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 1.37  Å
Source Organism:
Similar Structures:
Biological Unit for 3V1P: dimeric; determined by author and by software (PISA)
Molecular Components in 3V1P
Label Count Molecule
Proteins (2 molecules)
2
Orotidine 5'-phosphate Decarboxylase(Gene symbol: MTH_RS00570)
Molecule annotation
Chemicals (4 molecules)
1
2
2
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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