6ZC5

Human Adenovirus serotype D10 FiberKnob protein

6ZC5 の概要

• エントリーDOI: 10.2210/pdb6zc5/pdb
• 関連するPDBエントリー: 6STT
• 分子名称: Fiber (1 entity in total)
• 機能のキーワード: adenovirus, adv, hadv, hadv-d10, ad10, serotype 10, fiber, fiber-knob, fibre, knob domain, head, piv, protein iv, adenoviridae, viral protein
• 由来する生物種: Human adenovirus D10
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 256020.00

構造登録者

Baker, A.T.,Mundy, R.M.,Rizkallah, P.J.,Parker, A.L. (登録日: 2020-06-09, 公開日: 2021-06-30, 最終更新日: 2024-11-13)

主引用文献

Bates, E.A.,Davies, J.A.,Vanova, J.,Nestic, D.,Meniel, V.S.,Koushyar, S.,Cunliffe, T.G.,Mundy, R.M.,Moses, E.,Uusi-Kerttula, H.K.,Baker, A.T.,Cole, D.K.,Majhen, D.,Rizkallah, P.J.,Phesse, T.,Chester, J.D.,Parker, A.L.
Development of a low-seroprevalence, alpha v beta 6 integrin-selective virotherapy based on human adenovirus type 10.
Mol Ther Oncolytics, 25:43-56, 2022

PubMed Abstract: Oncolytic virotherapies (OV) hold immense clinical potential. OV based on human adenoviruses (HAdV) derived from HAdV with naturally low rates of pre-existing immunity will be beneficial for future clinical translation. We generated a low-seroprevalence HAdV-D10 serotype vector incorporating an αvβ6 integrin-selective peptide, A20, to target αvβ6-positive tumor cell types. HAdV-D10 has limited natural tropism. Structural and biological studies of HAdV-D10 knob protein highlighted low-affinity engagement with native adenoviral receptors CAR and sialic acid. HAdV-D10 fails to engage blood coagulation factor X, potentially eliminating "off-target" hepatic sequestration . We engineered an A20 peptide that selectively binds αvβ6 integrin into the DG loop of HAdV-D10 fiber knob. Assays in αvβ6+ cancer cell lines demonstrated significantly increased transduction mediated by αvβ6-targeted variants compared with controls, confirmed microscopically. HAdV-D10.A20 resisted neutralization by neutralizing HAdV-C5 sera. Systemic delivery of HAdV-D10.A20 resulted in significantly increased GFP expression in BT20 tumors. Replication-competent HAdV-D10.A20 demonstrated αvβ6 integrin-selective cell killing and . HAdV-D10 possesses characteristics of a promising virotherapy, combining low seroprevalence, weak receptor interactions, and reduced off-target uptake. Incorporation of an αvβ6 integrin-selective peptide resulted in HAdV-D10.A20, with significant potential for clinical translation.

PubMed: 35399606
DOI: 10.1016/j.omto.2022.03.007

実験手法

X-RAY DIFFRACTION (2.5 Å)