Ann Taylor Sandbox 7

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{{STRUCTURE_2ada| PDB=2ada | SCENE= }}
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[[Image:3d06.jpg|left|200px]]
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===ADENOSINE DEAMINASE===
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{{STRUCTURE_3d06| PDB=3d06 | SCENE= }}
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===Human p53 core domain with hot spot mutation R249S (I)===
 
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Adenosine deaminase is involved in the degradation of purine nucleotides. It is especially active in lympocytes, and mutation of adenosine deaminase results in severe immunodeficiency. Adenosine deaminase contains an eight stranded parallel alpha/beta barrel with the active site in a deep pocket at the beta-barrel COOH-terminal end. <ref>PMID:1925539 </ref> The active site contains a <scene name='36/365340/Zinc_cofactor/1'>zinc cofactor</scene>, which coordinates to the 6-hydroxyl of the transition state analogue, 6-hydroxyl, 1,6-dihydropurine ribonucleoside. The <scene name='36/365340/Zinc_cofactor/1'>zinc</scene> is coordinated to three histidine residues and an aspartic acid residue.
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The tumor suppressor protein p53 is mutated in more than 50% of invasive cancers. About 30% of the mutations are found in six major "hot spot" codons located in its DNA binding core domain. To gain structural insight into the deleterious effects of such mutations and their rescue by suppressor mutations, we determined the crystal structures of the p53 core domain incorporating the hot spot mutation R249S, the core domain incorporating R249S and a second-site suppressor mutation H168R (referred to as the double mutant R249S/H168R) and its sequence-specific complex with DNA and of the triple mutant R249S/H168R/T123A. The structural studies were accompanied by transactivation and apoptosis experiments. The crystal structures show that the region at the vicinity of the mutation site in the R249S mutant displays a range of conformations [wild-type (wt) and several mutant-type conformations] due to the loss of stabilizing interactions mediated by R249 in the wt protein. As a consequence, the protein surface that is critical to the formation of functional p53-DNA complexes, through protein-protein and protein-DNA interactions, is largely distorted in the mutant conformations, thus explaining the protein's "loss of function" as a transcription factor. The structure of this region is restored in both R249S/H168R and R249S/H168R/T123A and is further stabilized in the complex of R249S/H168R with DNA. Our functional data show that the introduction of H168R as a second-site suppressor mutation partially restores the transactivation capacity of the protein and that this effect is further amplified by the addition of a third-site mutation T123A. These findings together with previously reported data on wt and mutant p53 provide a structural framework for understanding p53 dysfunction as a result of oncogenic mutations and its rescue by suppressor mutations and for a potential drug design aimed at restoring wt activity to aberrant p53 proteins.
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The transition state analogue held in place mostly by polar interactions. The ribose group is close to the opening of the pocket, with the <scene name='36/365340/Purine_ring/1'>purine</scene> portion deeper in the pocket, close to the zinc. Nine hydrogen bonds stabilize the transition state-enzyme complex.
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Structural basis of restoring sequence-specific DNA binding and transactivation to mutant p53 by suppressor mutations., Suad O, Rozenberg H, Brosh R, Diskin-Posner Y, Kessler N, Shimon LJ, Frolow F, Liran A, Rotter V, Shakked Z, J Mol Biol. 2009 Jan 9;385(1):249-65. Epub 2008 Oct 30. PMID:18996393
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ADA is very stereoselective for the 6R isomer. This specificity is due to the location of the <scene name='36/365340/Zinc_cofactor/1'>catalytic zinc</scene>, <scene name='36/365340/Asp295/1'>Asp295</scene> and <scene name='36/365340/His_238/1'>His238</scene>. Interestingly, one face of the purine ring is exposed to polar groups and <scene name='36/365340/Zinc_cofactor/1'>zinc</scene>, while the other face is only exposed to nonpolar residues. The proposed catalytic mechanism has <scene name='36/365340/Asp295/1'>Asp295</scene> act as a general base, while the <scene name='36/365340/Zinc_cofactor/1'>zinc</scene> acts as an electrophile to activate the water molecule. <scene name='36/365340/Asp295/1'>Asp295</scene> and <scene name='36/365340/His_238/1'>His 238</scene> orients the water and stabilizes the charge of the attacking hydroxide. The protonated <scene name='36/365340/Glu217/1'>Glu217</scene> or the water hydrogen bonded to it could donate or share a proton with the N1 of the substrate.
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
 
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<references/>
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==Disease==
 
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Known disease associated with this structure: Adrenal cortical carcinoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Breast cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Colorectal cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Hepatocellular carcinoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Histiocytoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Li-Fraumeni syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Multiple malignancy syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Nasopharyngeal carcinoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Osteosarcoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Pancreatic cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Thyroid carcinoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]]
 
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==About this Structure==
 
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3D06 is a 1 chain structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3D06 OCA].
 
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==Reference==
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<references/>
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<ref group="xtra">PMID:18996393</ref><references group="xtra"/>
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[[Category: Homo sapiens]]
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[[Category: Frolow, F.]]
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[[Category: Rozenberg, H.]]
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[[Category: Shakked, Z.]]
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[[Category: Shimon, L J.W.]]
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[[Category: Suad, O.]]
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[[Category: Acetylation]]
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[[Category: Activator]]
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[[Category: Alternative splicing]]
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[[Category: Anti-oncogene]]
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[[Category: Apoptosis]]
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[[Category: Cell cycle]]
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[[Category: Covalent protein-rna linkage]]
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[[Category: Cytoplasm]]
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[[Category: Disease mutation]]
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[[Category: Dna-binding]]
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[[Category: Endoplasmic reticulum]]
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[[Category: Glycoprotein]]
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[[Category: Host-virus interaction]]
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[[Category: Li-fraumeni syndrome]]
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[[Category: Loop-sheet-helix motif]]
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[[Category: Metal-binding]]
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[[Category: Methylation]]
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[[Category: Mutant protein]]
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[[Category: Nucleus]]
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[[Category: P53]]
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[[Category: Phosphoprotein]]
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[[Category: Polymorphism]]
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[[Category: Transcription]]
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[[Category: Transcription regulation]]
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[[Category: Ubl conjugation]]
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[[Category: Zinc]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 21 10:44:12 2009''
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Current revision

PDB ID 2ada

Drag the structure with the mouse to rotate
2ada, resolution 2.40Å ()
Ligands: ,
Activity: Adenosine deaminase, with EC number 3.5.4.4
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml



ADENOSINE DEAMINASE

Adenosine deaminase is involved in the degradation of purine nucleotides. It is especially active in lympocytes, and mutation of adenosine deaminase results in severe immunodeficiency. Adenosine deaminase contains an eight stranded parallel alpha/beta barrel with the active site in a deep pocket at the beta-barrel COOH-terminal end. [1] The active site contains a , which coordinates to the 6-hydroxyl of the transition state analogue, 6-hydroxyl, 1,6-dihydropurine ribonucleoside. The is coordinated to three histidine residues and an aspartic acid residue.

The transition state analogue held in place mostly by polar interactions. The ribose group is close to the opening of the pocket, with the portion deeper in the pocket, close to the zinc. Nine hydrogen bonds stabilize the transition state-enzyme complex.

ADA is very stereoselective for the 6R isomer. This specificity is due to the location of the , and . Interestingly, one face of the purine ring is exposed to polar groups and , while the other face is only exposed to nonpolar residues. The proposed catalytic mechanism has act as a general base, while the acts as an electrophile to activate the water molecule. and orients the water and stabilizes the charge of the attacking hydroxide. The protonated or the water hydrogen bonded to it could donate or share a proton with the N1 of the substrate.


  1. ↑ Wilson DK, Rudolph FB, Quiocho FA. Atomic structure of adenosine deaminase complexed with a transition-state analog: understanding catalysis and immunodeficiency mutations. Science. 1991 May 31;252(5010):1278-84. PMID:1925539



Proteopedia Page Contributors and Editors (what is this?)

Peter A. Duden, Matt Routh, Ann Taylor

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