1BL4

FKBP MUTANT F36V COMPLEXED WITH REMODELED SYNTHETIC LIGAND

Summary for 1BL4

• Entry DOI: 10.2210/pdb1bl4/pdb
• Descriptor: PROTEIN (FK506 BINDING PROTEIN), {3-[3-(3,4-DIMETHOXY-PHENYL)-1-(1-{1-[2-(3,4,5-TRIMETHOXY-PHENYL)-BUTYRYL]-PIPERIDIN-2YL}-VINYLOXY)-PROPYL]-PHENOXY}-ACETIC ACID (3 entities in total)
• Functional Keywords: isomerase, rotamase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytosol : P62942
• Total number of polymer chains: 2
• Total formula weight: 24964.49

Authors

Hatada, M.H.,Clackson, T.,Yang, W.,Rozamus, L.W.,Amara, J.,Rollins, C.T.,Stevenson, L.F.,Magari, S.R.,Wood, S.A.,Courage, N.L.,Lu, X.,Cerasoli Junior, F.,Gilman, M.,Holt, D. (deposition date: 1998-07-23, release date: 1998-09-02, Last modification date: 2023-08-09)

Primary citation

Clackson, T.,Yang, W.,Rozamus, L.W.,Hatada, M.,Amara, J.F.,Rollins, C.T.,Stevenson, L.F.,Magari, S.R.,Wood, S.A.,Courage, N.L.,Lu, X.,Cerasoli Jr., F.,Gilman, M.,Holt, D.A.
Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity.
Proc.Natl.Acad.Sci.USA, 95:10437-10442, 1998

PubMed Abstract: 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.

PubMed: 9724721
DOI: 10.1073/pnas.95.18.10437

Experimental method

X-RAY DIFFRACTION (1.9 Å)