PDBsum entry 2gv9

Transferase

PDB id: 2gv9

Contents

Protein chains

981 a.a. *

1035 a.a. *

Ligands

SO4 ×2

GAI

Metals

_HG

Waters ×87

* Residue conservation analysis

PDB id:

2gv9

Name:

Transferase

Title:

Crystal structure of the herpes simplex virus type 1 DNA polymerase

Structure:

DNA polymerase. Chain: a, b. Engineered: yes

Source:

Human herpesvirus 1. Organism_taxid: 10306. Strain: kos. Gene: ul30. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.68Å R-factor: 0.225 R-free: 0.281

Authors:

S.Liu

Key ref:

S.Liu et al. (2006). Crystal structure of the herpes simplex virus 1 DNA polymerase. J Biol Chem, 281, 18193-18200. PubMed id: 16638752 DOI: 10.1074/jbc.M602414200

Date:

02-May-06 Release date: 16-May-06

Protein chain

P04292  (DPOL_HHV1K) -  DNA polymerase catalytic subunit from Human herpesvirus 1 (strain KOS)

Seq: 1235 a.a.

Struc: 981 a.a.

Protein chain

P04292  (DPOL_HHV1K) -  DNA polymerase catalytic subunit from Human herpesvirus 1 (strain KOS)

Seq: 1235 a.a.

Struc: 1035 a.a.

Enzyme reactions

• Enzyme class 2: Chains A, B: E.C.2.7.7.7 - DNA-directed Dna polymerase.
• Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
• Enzyme class 3: Chains A, B: E.C.3.1.26.4 - ribonuclease H.
• Reaction: Endonucleolytic cleavage to 5'-phosphomonoester.

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: 10.1074/jbc.M602414200

J Biol Chem 281:18193-18200 (2006)

PubMed id: 16638752

Crystal structure of the herpes simplex virus 1 DNA polymerase.

S.Liu, J.D.Knafels, J.S.Chang, G.A.Waszak, E.T.Baldwin, M.R.Deibel, D.R.Thomsen, F.L.Homa, P.A.Wells, M.C.Tory, R.A.Poorman, H.Gao, X.Qiu, A.P.Seddon.

ABSTRACT

Herpesviruses are the second leading cause of human viral diseases. Herpes Simplex Virus types 1 and 2 and Varicella-zoster virus produce neurotropic infections such as cutaneous and genital herpes, chickenpox, and shingles. Infections of a lymphotropic nature are caused by cytomegalovirus, HSV-6, HSV-7, and Epstein-Barr virus producing lymphoma, carcinoma, and congenital abnormalities. Yet another series of serious health problems are posed by infections in immunocompromised individuals. Common therapies for herpes viral infections employ nucleoside analogs, such as Acyclovir, and target the viral DNA polymerase, essential for viral DNA replication. Although clinically useful, this class of drugs exhibits a narrow antiviral spectrum, and resistance to these agents is an emerging problem for disease management. A better understanding of herpes virus replication will help the development of new safe and effective broad spectrum anti-herpetic drugs that fill an unmet need. Here, we present the first crystal structure of a herpesvirus polymerase, the Herpes Simplex Virus type 1 DNA polymerase, at 2.7 A resolution. The structural similarity of this polymerase to other alpha polymerases has allowed us to construct high confidence models of a replication complex of the polymerase and of Acyclovir as a DNA chain terminator. We propose a novel inhibition mechanism in which a representative of a series of non-nucleosidic viral polymerase inhibitors, the 4-oxo-dihydroquinolines, binds at the polymerase active site interacting non-covalently with both the polymerase and the DNA duplex.

Selected figure(s)

Figure 2.
FIGURE 2. Unique functional domains of herpes simplex 1 DNA polymerase. A, a ribbon diagram of the pre-NH[2]-terminal domain in cyan, with electrostatic surface representation of the putative single-stranded DNA binding groove. For clarity, only surfaces from NH[2]-terminal and exonuclease domains are shown. The DNA duplex is modeled. B, ribbon diagram of the NH[2]-terminal domain embedded in the electrostatic surface representation to show the putative RNA binding cleft. The motif is on the left.

Figure 3.
FIGURE 3. HSV POL replicating and inhibiting model. A, replicating model. The carbon atoms of HSV POL shown in stick are light gray, whereas those of primer DNA strand and dTTP are dark gray and those of the template are purple. Black dashed lines are shown for hydrogen bonds and ion interactions involving the incoming nucleotide and catalytic ions. B, model of Acyclovir·HSV POL dead-end complex. Hydrogen bonds involving Acyclovir are shown in black dashes. Key residues interacting with the Acyclovir-incorporated DNA, including the conserved KKKY motif (938-941), are shown. C, chemical structure of PNU-183792, a 4-oxo-DHQ type of herpes polymerase inhibitor. D, a novel inhibition mechanism of a family of broad spectrum inhibitor 4-oxo-DHQ. Residues interacting with inhibitor are highlighted.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 18193-18200) copyright 2006.

Figures were selected by the author.