6zl1
From Proteopedia
Crystal structure of human serum albumin in complex with the MCL-1 neutralizing Alphabody CMPX-383B
Structural highlights
DiseaseALBU_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.[1] [2] [3] [4] FunctionALBU_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.[5] Publication Abstract from PubMedThe 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[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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