| Structural highlights
4lcl is a 2 chain structure with sequence from Aspte. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | IPA |
| Related: | 3hl9, 3hlb, 3hlc, 3hld, 3hle, 3hlf, 3hlg, 4lcm |
| Gene: | lovD (ASPTE) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Publication Abstract from PubMed
Natural enzymes have evolved to perform their cellular functions under complex selective pressures, which often require their catalytic activities to be regulated by other proteins. We contrasted a natural enzyme, LovD, which acts on a protein-bound (LovF) acyl substrate, with a laboratory-generated variant that was transformed by directed evolution to accept instead a small free acyl thioester and no longer requires the acyl carrier protein. The resulting 29-mutant variant is 1,000-fold more efficient in the synthesis of the drug simvastatin than the wild-type LovD. This is to our knowledge the first nonpatent report of the enzyme currently used for the manufacture of simvastatin as well as the intermediate evolved variants. Crystal structures and microsecond-scale molecular dynamics simulations revealed the mechanism by which the laboratory-generated mutations free LovD from dependence on protein-protein interactions. Mutations markedly altered conformational dynamics of the catalytic residues, obviating the need for allosteric modulation by the acyl carrier LovF.
The role of distant mutations and allosteric regulation on LovD active site dynamics.,Jimenez-Oses G, Osuna S, Gao X, Sawaya MR, Gilson L, Collier SJ, Huisman GW, Yeates TO, Tang Y, Houk KN Nat Chem Biol. 2014 Jun;10(6):431-6. doi: 10.1038/nchembio.1503. Epub 2014 Apr, 13. PMID:24727900[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Jimenez-Oses G, Osuna S, Gao X, Sawaya MR, Gilson L, Collier SJ, Huisman GW, Yeates TO, Tang Y, Houk KN. The role of distant mutations and allosteric regulation on LovD active site dynamics. Nat Chem Biol. 2014 Jun;10(6):431-6. doi: 10.1038/nchembio.1503. Epub 2014 Apr, 13. PMID:24727900 doi:https://dx.doi.org/10.1038/nchembio.1503
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