4X1J

X-ray crystal structure of the dimeric BMP antagonist NBL1

4X1J の概要

• エントリーDOI: 10.2210/pdb4x1j/pdb
• 関連するPDBエントリー: 4JPH
• 分子名称: Neuroblastoma suppressor of tumorigenicity 1, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• 機能のキーワード: bmp antagonist, dan family, cystine-knot, bmp binding protein
• 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: 25749.35

構造登録者

Thompson, T.B.,Nolan, K.,Kattamuri, C. (登録日: 2014-11-24, 公開日: 2015-01-14, 最終更新日: 2024-11-20)

主引用文献

Nolan, K.,Kattamuri, C.,Luedeke, D.M.,Angerman, E.B.,Rankin, S.A.,Stevens, M.L.,Zorn, A.M.,Thompson, T.B.
Structure of Neuroblastoma Suppressor of Tumorigenicity 1 (NBL1): INSIGHTS FOR THE FUNCTIONAL VARIABILITY ACROSS BONE MORPHOGENETIC PROTEIN (BMP) ANTAGONISTS.
J.Biol.Chem., 290:4759-4771, 2015

PubMed Abstract: Bone morphogenetic proteins (BMPs) are antagonized through the action of numerous extracellular protein antagonists, including members from the differential screening-selected gene aberrative in neuroblastoma (DAN) family. In vivo, misregulation of the balance between BMP signaling and DAN inhibition can lead to numerous disease states, including cancer, kidney nephropathy, and pulmonary arterial hypertension. Despite this importance, very little information is available describing how DAN family proteins effectively inhibit BMP ligands. Furthermore, our understanding for how differences in individual DAN family members arise, including affinity and specificity, remains underdeveloped. Here, we present the structure of the founding member of the DAN family, neuroblastoma suppressor of tumorigenicity 1 (NBL1). Comparing NBL1 to the structure of protein related to Dan and Cerberus (PRDC), a more potent BMP antagonist within the DAN family, a number of differences were identified. Through a mutagenesis-based approach, we were able to correlate the BMP binding epitope in NBL1 with that in PRDC, where introduction of specific PRDC amino acids in NBL1 (A58F and S67Y) correlated with a gain-of-function inhibition toward BMP2 and BMP7, but not GDF5. Although NBL1(S67Y) was able to antagonize BMP7 as effectively as PRDC, NBL1(S67Y) was still 32-fold weaker than PRDC against BMP2. Taken together, this data suggests that alterations in the BMP binding epitope can partially account for differences in the potency of BMP inhibition within the DAN family.

PubMed: 25561725
DOI: 10.1074/jbc.M114.628412

実験手法

X-RAY DIFFRACTION (2.5 Å)