PDBsum entry 4ztz

DNA binding protein/DNA

PDB id: 4ztz

Contents

Protein chains

983 a.a.

363 a.a.

DNA/RNA

Ligands

DCP

Metals

_MG ×2

PDB id:

4ztz

Name:

DNA binding protein/DNA

Title:

Structural basis for processivity and antiviral drug toxicity in human mitochondrial DNA replicase

Structure:

DNA polymerase subunit gamma-1. Chain: a. Fragment: unp residues 30-1239. Synonym: mitochondrial DNA polymerase catalytic subunit,polg-alpha. Engineered: yes. DNA polymerase subunit gamma-2, mitochondrial. Chain: b, c. Synonym: DNA polymerase gamma accessory 55 kda subunit,p55, mitochondrial DNA polymerase accessory subunit,mtpolb,polg-beta.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: polg, mdp1, polg1, polga. Expressed in: insect cell expression vector ptie1. Expression_system_taxid: 266783. Gene: polg2, mtpolb. Synthetic: yes. Synthetic construct.

Resolution:

3.44Å R-factor: 0.281 R-free: 0.320

Authors:

M.R.Szymanski,Y.W.Yin

Key ref:

M.R.Szymanski et al. (2015). Structural basis for processivity and antiviral drug toxicity in human mitochondrial DNA replicase. Embo J, 34, 1959-1970. PubMed id: 26056153 DOI: 10.15252/embj.201591520

Date:

15-May-15 Release date: 23-Sep-15

Protein chain

P54098  (DPOG1_HUMAN) -  DNA polymerase subunit gamma-1 from Homo sapiens

Seq: 1239 a.a.

Struc: 983 a.a.*

Protein chains

Q9UHN1  (DPOG2_HUMAN) -  DNA polymerase subunit gamma-2, mitochondrial from Homo sapiens

Seq: 485 a.a.

Struc: 363 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DNA/RNA chains

G-C-G-A-T-A-C-G-G-C-A-C-T-G-G-C-C-C-T-C-G-T-C-T-T 25 bases

A-A-G-A-C-G-A-G-G-G-C-C-A-G-T-G-C-C-G-T-A-DOC 22 bases

Enzyme reactions

• Enzyme class 1: Chain A: E.C.2.7.7.7 - DNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
• Enzyme class 2: Chains B, C: E.C.?

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.15252/embj.201591520

Embo J 34:1959-1970 (2015)

PubMed id: 26056153

Structural basis for processivity and antiviral drug toxicity in human mitochondrial DNA replicase.

M.R.Szymanski, V.B.Kuznetsov, C.Shumate, Q.Meng, Y.S.Lee, G.Patel, S.Patel, Y.W.Yin.

ABSTRACT

The human DNA polymerase gamma (Pol γ) is responsible for DNA replication in mitochondria. Pol γ is particularly susceptible to inhibition by dideoxynucleoside-based inhibitors designed to fight viral infection. Here, we report crystal structures of the replicating Pol γ-DNA complex bound to either substrate or zalcitabine, an inhibitor used for HIV reverse transcriptase. The structures reveal that zalcitabine binds to the Pol γ active site almost identically to the substrate dCTP, providing a structural basis for Pol γ-mediated drug toxicity. When compared to the apo form, Pol γ undergoes intra- and inter-subunit conformational changes upon formation of the ternary complex with primer/template DNA and substrate. We also find that the accessory subunit Pol γB, which lacks intrinsic enzymatic activity and does not contact the primer/template DNA directly, serves as an allosteric regulator of holoenzyme activities. The structures presented here suggest a mechanism for processivity of the holoenzyme and provide a model for understanding the deleterious effects of Pol γ mutations in human disease. Crystal structures of the mitochondrial DNA polymerase, Pol γ, in complex with substrate or antiviral inhibitor zalcitabine provide a basis for understanding Pol γ-mediated drug toxicity.