1BL4

FKBP MUTANT F36V COMPLEXED WITH REMODELED SYNTHETIC LIGAND


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.188 

wwPDB Validation   3D Report Full Report


This is version 1.5 of the entry. See complete history


Literature

Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity.

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.

(1998) Proc Natl Acad Sci U S A 95: 10437-10442

  • DOI: https://doi.org/10.1073/pnas.95.18.10437
  • Primary Citation of Related Structures:  
    1BL4

  • 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.


  • Organizational Affiliation

    ARIAD Gene Therapeutics, Inc., 26 Landsdowne Street, Cambridge, MA 02139, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PROTEIN (FK506 BINDING PROTEIN)
A, B
107Homo sapiensMutation(s): 1 
EC: 5.2.1.8
UniProt & NIH Common Fund Data Resources
Find proteins for P62942 (Homo sapiens)
Explore P62942 
Go to UniProtKB:  P62942
PHAROS:  P62942
GTEx:  ENSG00000088832 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP62942
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
AP1
Query on AP1

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
{3-[3-(3,4-DIMETHOXY-PHENYL)-1-(1-{1-[2-(3,4,5-TRIMETHOXY-PHENYL)-BUTYRYL]-PIPERIDIN-2YL}-VINYLOXY)-PROPYL]-PHENOXY}-ACETIC ACID
C38 H47 N O11
XCCRAOPQCACRFC-OIFRRMEBSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
AP1 Binding MOAD:  1BL4 IC50: 1.8 (nM) from 1 assay(s)
PDBBind:  1BL4 IC50: 1.8 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.188 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 32.73α = 62.61
b = 41.85β = 82.75
c = 43.59γ = 85.29
Software Package:
Software NamePurpose
AMoREphasing
X-PLORrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 1998-09-02
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2018-04-18
    Changes: Data collection
  • Version 1.4: 2021-11-03
    Changes: Database references, Derived calculations
  • Version 1.5: 2023-08-09
    Changes: Data collection, Refinement description