Atomic structure of adenosine deaminase complexed with a transition-state analog: Understanding catalysis and immunodeficiency mutations

David K. Wilson, Frederick B. Rudolph, Florante A. Quiocho

Research output: Contribution to journalArticle

409 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1278-1284
Number of pages7
JournalScience
Volume252
Issue number5010
StatePublished - May 31 1991
Externally publishedYes

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Adenosine Deaminase
Catalysis
Zinc
Mutation
Inborn Genetic Diseases
Enzymes
Viperidae
Point Mutation
Hydroxyl Radical
Hydrogen

ASJC Scopus subject areas

  • General

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 journalArticle

Wilson, David K. ; Rudolph, Frederick B. ; Quiocho, Florante A. / Atomic structure of adenosine deaminase complexed with a transition-state analog : Understanding catalysis and immunodeficiency mutations. In: Science. 1991 ; Vol. 252, No. 5010. pp. 1278-1284.
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