6zl1

Crystal structure of human serum albumin in complex with the MCL-1 neutralizing Alphabody CMPX-383B

spinqualitylabelsall models 6zl1, resolution 3.27Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6zl1 is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.272Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease ALBU_HUMAN Defects in ALB are a cause of familial dysalbuminemic hyperthyroxinemia (FDH) [MIM:103600. FDH is a form of euthyroid hyperthyroxinemia that is due to increased affinity of ALB for T(4). It is the most common cause of inherited euthyroid hyperthyroxinemia in Caucasian population. Function ALBU_HUMAN Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc. Publication Abstract from PubMed The therapeutic scope of antibody and nonantibody protein scaffolds is still prohibitively limited against intracellular drug targets. Here, we demonstrate that the Alphabody scaffold can be engineered into a cell-penetrating protein antagonist against induced myeloid leukemia cell differentiation protein MCL-1, an intracellular target in cancer, by grafting the critical B-cell lymphoma 2 homology 3 helix of MCL-1 onto the Alphabody and tagging the scaffold's termini with designed cell-penetration polypeptides. Introduction of an albumin-binding moiety extended the serum half-life of the engineered Alphabody to therapeutically relevant levels, and administration thereof in mouse tumor xenografts based on myeloma cell lines reduced tumor burden. Crystal structures of such a designed Alphabody in complex with MCL-1 and serum albumin provided the structural blueprint of the applied design principles. Collectively, we provide proof of concept for the use of Alphabodies against intracellular disease mediators, which, to date, have remained in the realm of small-molecule therapeutics. Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting.,Pannecoucke E, Van Trimpont M, Desmet J, Pieters T, Reunes L, Demoen L, Vuylsteke M, Loverix S, Vandenbroucke K, Alard P, Henderikx P, Deroo S, Baatz F, Lorent E, Thiolloy S, Somers K, McGrath Y, Van Vlierberghe P, Lasters I, Savvides SN Sci Adv. 2021 Mar 26;7(13):eabe1682. doi: 10.1126/sciadv.abe1682. Print 2021 Mar. PMID:33771865 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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