Abstract
The crystal structure of a murine adenosine deaminase complexed with 6-hydroxyl-1,6-dihydropurine ribonucleoside, a nearly ideal transition-state analog, has been determined and refined at 2.4 angstrom resolution. The structure is folded as an eight-stranded parallel α/β barrel with a deep pocket at the β-barrel COOH-terminal end wherein the inhibitor and a zinc are bound and completely sequestered. The presence of the zinc cofactor and the precise structure of the bound analog were not previously known. The 6R isomer of the analog is very tightly held in place by the coordination of the 6-hydroxyl to the zinc and the formation of nine hydrogen bonds. On the basis of the structure of the complex a stereoselective addition-elimination or SN2 mechanism of the enzyme is proposed with the zinc atom and the Glu and Asp residues playing key roles. A molecular explanation of a hereditary disease caused by several point mutations of an enzyme is also presented.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1278-1284 |
| Number of pages | 7 |
| Journal | Science |
| Volume | 252 |
| Issue number | 5010 |
| State | Published - May 31 1991 |
| Externally published | Yes |
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Cite this
Atomic structure of adenosine deaminase complexed with a transition-state analog : Understanding catalysis and immunodeficiency mutations. / Wilson, David K.; Rudolph, Frederick B.; Quiocho, Florante A.
In: Science, Vol. 252, No. 5010, 31.05.1991, p. 1278-1284.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Atomic structure of adenosine deaminase complexed with a transition-state analog
T2 - Understanding catalysis and immunodeficiency mutations
AU - Wilson, David K.
AU - Rudolph, Frederick B.
AU - Quiocho, Florante A.
PY - 1991/5/31
Y1 - 1991/5/31
N2 - The crystal structure of a murine adenosine deaminase complexed with 6-hydroxyl-1,6-dihydropurine ribonucleoside, a nearly ideal transition-state analog, has been determined and refined at 2.4 angstrom resolution. The structure is folded as an eight-stranded parallel α/β barrel with a deep pocket at the β-barrel COOH-terminal end wherein the inhibitor and a zinc are bound and completely sequestered. The presence of the zinc cofactor and the precise structure of the bound analog were not previously known. The 6R isomer of the analog is very tightly held in place by the coordination of the 6-hydroxyl to the zinc and the formation of nine hydrogen bonds. On the basis of the structure of the complex a stereoselective addition-elimination or SN2 mechanism of the enzyme is proposed with the zinc atom and the Glu and Asp residues playing key roles. A molecular explanation of a hereditary disease caused by several point mutations of an enzyme is also presented.
AB - The crystal structure of a murine adenosine deaminase complexed with 6-hydroxyl-1,6-dihydropurine ribonucleoside, a nearly ideal transition-state analog, has been determined and refined at 2.4 angstrom resolution. The structure is folded as an eight-stranded parallel α/β barrel with a deep pocket at the β-barrel COOH-terminal end wherein the inhibitor and a zinc are bound and completely sequestered. The presence of the zinc cofactor and the precise structure of the bound analog were not previously known. The 6R isomer of the analog is very tightly held in place by the coordination of the 6-hydroxyl to the zinc and the formation of nine hydrogen bonds. On the basis of the structure of the complex a stereoselective addition-elimination or SN2 mechanism of the enzyme is proposed with the zinc atom and the Glu and Asp residues playing key roles. A molecular explanation of a hereditary disease caused by several point mutations of an enzyme is also presented.
UR - http://www.scopus.com/inward/record.url?scp=0026434561&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0026434561&partnerID=8YFLogxK
M3 - Article
C2 - 1925539
AN - SCOPUS:0026434561
VL - 252
SP - 1278
EP - 1284
JO - Science
JF - Science
SN - 0036-8075
IS - 5010
ER -