6CDX

High-resolution crystal structure of fluoropropylated cystine knot, binding to alpha-5 beta-6 integrin

6CDX の概要

• エントリーDOI: 10.2210/pdb6cdx/pdb
• 関連するPDBエントリー: 2N8B 2N8C
• 分子名称: cystine knot (fluoropropylated) (2 entities in total)
• 機能のキーワード: cysteine, disulfides, alpha-5 beta-6 integrin binding epitope, cancer imaging, protein binding
• 由来する生物種: Momordica cochinchinensis (Spiny bitter cucumber); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 7833.00

構造登録者

Kimura, R.,Nix, J.,Bongura, C.,Chakraborti, S.,Gambhir, S.,Filipp, F.V. (登録日: 2018-02-09, 公開日: 2019-08-14, 最終更新日: 2024-10-23)

主引用文献

Kimura, R.H.,Wang, L.,Shen, B.,Huo, L.,Tummers, W.,Filipp, F.V.,Guo, H.H.,Haywood, T.,Abou-Elkacem, L.,Baratto, L.,Habte, F.,Devulapally, R.,Witney, T.H.,Cheng, Y.,Tikole, S.,Chakraborti, S.,Nix, J.,Bonagura, C.A.,Hatami, N.,Mooney, J.J.,Desai, T.,Turner, S.,Gaster, R.S.,Otte, A.,Visser, B.C.,Poultsides, G.A.,Norton, J.,Park, W.,Stolowitz, M.,Lau, K.,Yang, E.,Natarajan, A.,Ilovich, O.,Srinivas, S.,Srinivasan, A.,Paulmurugan, R.,Willmann, J.,Chin, F.T.,Cheng, Z.,Iagaru, A.,Li, F.,Gambhir, S.S.
Evaluation of integrin alpha v beta6cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis.
Nat Commun, 10:4673-4673, 2019

PubMed Abstract: Advances in precision molecular imaging promise to transform our ability to detect, diagnose and treat disease. Here, we describe the engineering and validation of a new cystine knot peptide (knottin) that selectively recognizes human integrin αvβ with single-digit nanomolar affinity. We solve its 3D structure by NMR and x-ray crystallography and validate leads with 3 different radiolabels in pre-clinical models of cancer. We evaluate the lead tracer's safety, biodistribution and pharmacokinetics in healthy human volunteers, and show its ability to detect multiple cancers (pancreatic, cervical and lung) in patients at two study locations. Additionally, we demonstrate that the knottin PET tracers can also detect fibrotic lung disease in idiopathic pulmonary fibrosis patients. Our results indicate that these cystine knot PET tracers may have potential utility in multiple disease states that are associated with upregulation of integrin αβ.

PubMed: 31611594
DOI: 10.1038/s41467-019-11863-w

実験手法

X-RAY DIFFRACTION (1 Å)