6OMO

Human BMP6 homodimer

6OMO の概要

• エントリーDOI: 10.2210/pdb6omo/pdb
• 分子名称: Bone morphogenetic protein 6, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ISOPROPYL ALCOHOL, ... (6 entities in total)
• 機能のキーワード: bmp, bone morphogenetic protein, cytokine
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 24771.57

構造登録者

Juo, Z.S.,Seeherman, H. (登録日: 2019-04-19, 公開日: 2019-05-08, 最終更新日: 2024-10-16)

主引用文献

Seeherman, H.J.,Berasi, S.P.,Brown, C.T.,Martinez, R.X.,Juo, Z.S.,Jelinsky, S.,Cain, M.J.,Grode, J.,Tumelty, K.E.,Bohner, M.,Grinberg, O.,Orr, N.,Shoseyov, O.,Eyckmans, J.,Chen, C.,Morales, P.R.,Wilson, C.G.,Vanderploeg, E.J.,Wozney, J.M.
A BMP/activin A chimera is superior to native BMPs and induces bone repair in nonhuman primates when delivered in a composite matrix.
Sci Transl Med, 11:-, 2019

PubMed Abstract: Bone morphogenetic protein (BMP)/carriers approved for orthopedic procedures achieve efficacy superior or equivalent to autograft bone. However, required supraphysiological BMP concentrations have been associated with potential local and systemic adverse events. Suboptimal BMP/receptor binding and rapid BMP release from approved carriers may contribute to these outcomes. To address these issues and improve efficacy, we engineered chimeras with increased receptor binding by substituting BMP-6 and activin A receptor binding domains into BMP-2 and optimized a carrier for chimera retention and tissue ingrowth. BV-265, a BMP-2/BMP-6/activin A chimera, demonstrated increased binding affinity to BMP receptors, including activin-like kinase-2 (ALK2) critical for bone formation in people. BV-265 increased BMP intracellular signaling, osteogenic activity, and expression of bone-related genes in murine and human cells to a greater extent than BMP-2 and was not inhibited by BMP antagonist noggin or gremlin. BV-265 induced larger ectopic bone nodules in rats compared to BMP-2 and was superior to BMP-2, BMP-2/6, and other chimeras in nonhuman primate bone repair models. A composite matrix (CM) containing calcium-deficient hydroxyapatite granules suspended in a macroporous, fenestrated, polymer mesh-reinforced recombinant human type I collagen matrix demonstrated improved BV-265 retention, minimal inflammation, and enhanced handling. BV-265/CM was efficacious in nonhuman primate bone repair models at concentrations ranging from / to / of the BMP-2/absorbable collagen sponge (ACS) concentration approved for clinical use. Initial toxicology studies were negative. These results support evaluations of BV-265/CM as an alternative to BMP-2/ACS in clinical trials for orthopedic conditions requiring augmented healing.

PubMed: 31019025
DOI: 10.1126/scitranslmed.aar4953

実験手法

X-RAY DIFFRACTION (2.8 Å)