1bl4
From Proteopedia
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FKBP MUTANT F36V COMPLEXED WITH REMODELED SYNTHETIC LIGAND
Overview
FKBP ligand homodimers can be used to activate signaling events inside, cells and animals that have been engineered to express fusions between, appropriate signaling domains and FKBP. However, use of these dimerizers, in vivo is potentially limited by ligand binding to endogenous FKBP. We, have designed ligands that bind specifically to a mutated FKBP over the, wild-type protein by remodeling an FKBP-ligand interface to introduce a, specificity binding pocket. A compound bearing an ethyl substituent in, place of a carbonyl group exhibited sub-nanomolar affinity and 1,000-fold, selectivity for a mutant FKBP with a compensating truncation of a, phenylalanine residue. Structural and functional analysis of the new, pocket showed that recognition is surprisingly relaxed, with the modified, ligand only partially filling the engineered cavity. We incorporated the, specificity pocket into a fusion protein containing FKBP and the, intracellular domain of the Fas receptor. Cells expressing this modified, chimeric protein potently underwent apoptosis in response to AP1903, a, homodimer of the modified ligand, both in culture and when implanted into, mice. Remodeled dimerizers such as AP1903 are ideal reagents for, controlling the activities of cells that have been modified by gene, therapy procedures, without interference from endogenous FKBP.
About this Structure
1BL4 is a Single protein structure of sequence from Homo sapiens with AP1 as ligand. Active as Peptidylprolyl isomerase, with EC number 5.2.1.8 Full crystallographic information is available from OCA.
Reference
Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity., Clackson T, Yang W, Rozamus LW, Hatada M, Amara JF, Rollins CT, Stevenson LF, Magari SR, Wood SA, Courage NL, Lu X, Cerasoli F Jr, Gilman M, Holt DA, Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10437-42. PMID:9724721
Page seeded by OCA on Tue Nov 20 11:44:10 2007
