4x1j

X-ray crystal structure of the dimeric BMP antagonist NBL1

spinqualitylabelsall models 4x1j, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4x1j is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NAG Related: 4jph Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [NBL1_HUMAN] Possible candidate as a tumor suppressor gene of neuroblastoma. May play an important role in preventing cells from entering the final stage (G1/S) of the transformation process. Publication Abstract from PubMed 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 towards BMP2 and BMP7, but not GDF5. While NBL1S67Y was able to antagonize BMP7 as effectively as PRDC, NBL1S67Y was still 40-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. Structure of Neuroblastoma Suppressor of Tumorigenicity 1 (NBL1): Insights for the Functional Variability Across Bone Morphogenetic Protein (BMP) Antagonists.,Nolan K, Kattamuri C, Luedeke DM, Angerman EB, Rankin SA, Stevens ML, Zorn AM, Thompson TB J Biol Chem. 2015 Jan 5. pii: jbc.M114.628412. PMID:25561725 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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