title: Zinc-mediated binding of a low-molecular-weight stabilizer of the host anti-viral factor apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G.
abstract: Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G, A3G), is a human anti-virus restriction protein which works deaminase-dependently and -independently. A3G is known to be ubiquitinated by HIV-1 viral infectivity factor (Vif) protein, leading to proteasomal degradation. A3G contains two zinc ions at the N-terminal domain and the C-terminal domain. Four lysine residues, K(297), K(301), K(303), and K(334), are known to be required for Vif-mediated A3G ubiquitination and degradation. Previously, we reported compound SN-1, a zinc chelator that increases steady-state expression level of A3G in the presence of Vif. In this study, we prepared Biotin-SN-1, a biotinylated derivative of SN-1, to study the SN-1-A3G interaction. A pull-down assay revealed that Biotin-SN-1 bound A3G. A zinc-abstraction experiment indicated that SN-1 binds to the zinc site of A3G. We carried out a SN-1-A3G docking study using molecular operating environment. The calculations revealed that SN-1 binds to the C-terminal domain through Zn(2+), H(216), P(247), C(288), and Y(315). Notably, SN-1-binding covers the H(257), E(259), C(288), and C(291) residues that participate in zinc-mediated deamination, and the ubiquitination regions of A3G. The binding of SN-1 presumably perturbs the secondary structure between C(288) and Y(315), leading to less efficient ubiquitination.
authors.affiliation: Department of Bioorganic Medicinal Chemistry, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Mohamed O
authors.initials: MO
authors.lastname: Radwan
authors.affiliation: Department of Bioorganic Medicinal Chemistry, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Sonoda
authors.affiliation: Department of Bioorganic Medicinal Chemistry, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ejima
authors.affiliation: Department of Bioorganic Medicinal Chemistry, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Department of Bioorganic Medicinal Chemistry, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Koga
authors.affiliation: Department of Bioorganic Medicinal Chemistry, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: Research Institute for Drug Discovery, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan. Electronic address: mfujita@kumamoto-u.ac.jp.
authors.forename: Mikako
authors.initials: M
authors.lastname: Fujita
authors.affiliation: Department of Bioorganic Medicinal Chemistry, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan. Electronic address: motsuka@gpo.kumamoto-u.ac.jp.
authors.forename: Masami
authors.initials: M
authors.lastname: Otsuka
mesh_terms: D000071480:APOBEC-3G Deaminase / Q000737:chemistry*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D008970:Molecular Weight; D015032:Zinc / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D015032:Zinc
keywords: APOBEC3G; Biotin–avidin technology; HIV; Host anti-viral factor; Molecular docking; Zinc