PDBsum entry 1a4m

Hydrolase

PDB id: 1a4m

Contents

Protein chains

349 a.a. *

Ligands

PRH ×4

Metals

_ZN ×4

Waters ×1065

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Complexes of adenosine deaminase with two potent inhibitors: x-Ray structures in four independent molecules at ph of maximum activity.

Authors

Z.Wang, F.A.Quiocho.

Ref.

Biochemistry, 1998, 37, 8314-8324. [DOI no: 10.1021/bi980324o]

PubMed id

9622483

Abstract

Adenosine deaminase, which catalyzes the irreversible hydrolytic deamination of adenosine nucleosides to inosine nucleosides and ammonia, is a key enzyme in purine metabolism and lymphoid development. The X-ray structures of murine adenosine deaminase with bound potent inhibitors (Ki values approximately 10(-13) M) (8R)-hydroxyl-2'-deoxycoformycin (pentostatin), a transition state analogue, and (6S)-hydroxyl-1,6-dihydropurine riboside, a reaction coordinate analogue, have been determined and refined to resolutions of 2.6 and 1.95 A, respectively. Crystals of both complexes were obtained at pH 7, where the enzyme is fully active, in an identical space group with the asymmetric unit containing four molecules. In addition to the very high degree of similarity between the four independent molecules in each complex structure, there is also considerable structural similarity of the complex with the dihydropurine riboside with that of an identical complex previously determined at pH 4.2 where the enzyme is 20% active. The interactions between the enzyme and the two analogues are extremely similar. These include the coordination of the 8R- or 6S-hydroxyl group of the analogues to the Zn2+ which mainly contributes to the strong potency and very high degree of stereospecificity of inhibition by these analogues. The interactions are further indicative of the structural and chemical requirements of substrates. These structures and recent site-directed mutagenesis have further shed light on the catalytic mechanism of the enzyme.

Secondary reference #1

Title

A pre-Transition-State mimic of an enzyme: X-Ray structure of adenosine deaminase with bound 1-Deazaadenosine and zinc-Activated water.

Authors

D.K.Wilson, F.A.Quiocho.

Ref.

Biochemistry, 1993, 32, 1689-1694. [DOI no: 10.1021/bi00058a001]

PubMed id

8439534

Secondary reference #2

Title

Refined 2.5 a structure of murine adenosine deaminase at ph 6.0.

Authors

A.J.Sharff, D.K.Wilson, Z.Chang, F.A.Quiocho.

Ref.

J Mol Biol, 1992, 226, 917-921. [DOI no: 10.1016/0022-2836(92)91040-V]

PubMed id

1518061

Figure 3.
Figure 3. Stereo epresentation of the active site complxed with 6-hydroxyl-1,6-dihydropurine ribonucleside. The H 4.2 structure is shown n black wit the pH 60 structure superimposed in red.

Figure 4.
Figure 4. Schematic epresentation of the interactions between ADA and 6-hydroxyl-,6-dihydropurine ribonuc- leoside. umbers near broken lines indicate distances (in ) between efined on-hydrogen atoms in the pH 42 strcture Where different, the equivalent distances in the pH 60 structure are given in arenthesis.

The above figures are reproduced from the cited reference with permission from Elsevier

Secondary reference #3

Title

Atomic structure of adenosine deaminase complexed with a transition-State analog: understanding catalysis and immunodeficiency mutations.

Authors

D.K.Wilson, F.B.Rudolph, F.A.Quiocho.

Ref.

Science, 1991, 252, 1278-1284. [DOI no: 10.1126/science.1925539]

PubMed id

1925539