1Z4M

Structure of the D41N variant of the human mitochondrial deoxyribonucleotidase in complex with uridine 5'-monophosphate

Summary for 1Z4M

• Entry DOI: 10.2210/pdb1z4m/pdb
• Related: 1Z4I 1Z4J 1Z4K 1Z4L 1Z4P 1Z4Q
• Descriptor: 5'(3')-deoxyribonucleotidase, MAGNESIUM ION, URIDINE-5'-MONOPHOSPHATE, ... (5 entities in total)
• Functional Keywords: alfa beta fold, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Mitochondrion: Q9NPB1
• Total number of polymer chains: 1
• Total formula weight: 23280.72

Authors

Wallden, K.,Ruzzenente, B.,Rinaldo-Matthis, A.,Bianchi, V.,Nordlund, P. (deposition date: 2005-03-16, release date: 2005-07-26, Last modification date: 2024-05-29)

Primary citation

Wallden, K.,Ruzzenente, B.,Rinaldo-Matthis, A.,Bianchi, V.,Nordlund, P.
Structural basis for substrate specificity of the human mitochondrial deoxyribonucleotidase
STRUCTURE, 13:1081-1088, 2005

PubMed Abstract: The human mitochondrial deoxyribonucleotidase catalyzes the dephosphorylation of thymidine and deoxyuridine monophosphates and participates in the regulation of the dTTP pool in mitochondria. We present seven structures of the inactive D41N variant of this enzyme in complex with thymidine 3'-monophosphate, thymidine 5'-monophosphate, deoxyuridine 5'-monophosphate, uridine 5'-monophosphate, deoxyguanosine 5'-monophosphate, uridine 2'-monophosphate, and the 5'-monophosphate of the nucleoside analog 3'-deoxy 2'3'-didehydrothymidine, and we draw conclusions about the substrate specificity based on comparisons with enzyme activities. We show that the enzyme's specificity for the deoxyribo form of nucleoside 5'-monophosphates is due to Ile-133, Phe-49, and Phe-102, which surround the 2' position of the sugar and cause an energetically unfavorable environment for the 2'-hydroxyl group of ribonucleoside 5'-monophosphates. The close binding of the 3'-hydroxyl group of nucleoside 5'-monophosphates to the enzyme indicates that nucleoside analog drugs that are substituted with a bulky group at this position will not be good substrates for this enzyme.

PubMed: 16004879
DOI: 10.1016/j.str.2005.04.023

Experimental method

X-RAY DIFFRACTION (1.7 Å)