TY - JOUR
T1 - Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes
AU - Harel, Michal
AU - Aharoni, Amir
AU - Gaidukov, Leonid
AU - Brumshtein, Boris
AU - Khersonsky, Olga
AU - Meged, Ran
AU - Dvir, Hay
AU - Ravelli, Raimond B.G.
AU - McCarthy, Andrew
AU - Toker, Lilly
AU - Silman, Israel
AU - Sussman, Joel L.
AU - Tawfik, Dan S.
N1 - Funding Information:
We acknowledge financial support by the Minerva Foundation and the Israel Science Foundation to D.S.T. and US army Medical Research & Materiel Command to I.S. and J.L.S. The structure was determined in collaboration with the Israel Structural Proteomics Center, supported by the Israel Ministry of Science & Technology, the European Commission Structural Proteomics Project (SPINE) and the Divadol Foundation. J.L.S. is the Morton and Gladys Pickman Professor of Structural Biology.
PY - 2004/5/1
Y1 - 2004/5/1
N2 - Members of the serum paraoxonase (PON) family have been identified in mammals and other vertebrates, and in invertebrates. PONs exhibit a wide range of physiologically important hydrolytic activities, including drug metabolism and detoxification of nerve agents. PON1 and PON3 reside on high-density lipoprotein (HDL, 'good cholesterol') and are involved in the prevention of atherosclerosis. We describe the first crystal structure of a PON family member, a variant of PON1 obtained by directed evolution, at a resolution of 2.2 Å. PON1 is a six-bladed β-propeller with a unique active site lid that is also involved in HDL binding. The three-dimensional structure and directed evolution studies permit a detailed description of PON1's active site and catalytic mechanism, which are reminiscent of secreted phospholipase A2, and of the routes by which PON family members diverged toward different substrate and reaction selectivities.
AB - Members of the serum paraoxonase (PON) family have been identified in mammals and other vertebrates, and in invertebrates. PONs exhibit a wide range of physiologically important hydrolytic activities, including drug metabolism and detoxification of nerve agents. PON1 and PON3 reside on high-density lipoprotein (HDL, 'good cholesterol') and are involved in the prevention of atherosclerosis. We describe the first crystal structure of a PON family member, a variant of PON1 obtained by directed evolution, at a resolution of 2.2 Å. PON1 is a six-bladed β-propeller with a unique active site lid that is also involved in HDL binding. The three-dimensional structure and directed evolution studies permit a detailed description of PON1's active site and catalytic mechanism, which are reminiscent of secreted phospholipase A2, and of the routes by which PON family members diverged toward different substrate and reaction selectivities.
UR - http://www.scopus.com/inward/record.url?scp=2342569704&partnerID=8YFLogxK
U2 - 10.1038/nsmb767
DO - 10.1038/nsmb767
M3 - Article
AN - SCOPUS:2342569704
SN - 1545-9993
VL - 11
SP - 412
EP - 419
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 5
ER -