Rational design of proteins that exchange on functional timescales.


Abstract

Proteins are intrinsically dynamic molecules that can exchange between multiple conformational states, enabling them to carry out complex molecular processes with extreme precision and efficiency. Attempts to design novel proteins with tailored functions have mostly failed to yield efficiencies matching those found in nature because standard methods do not allow the design of exchange between necessary conformational states on a functionally relevant timescale. Here we developed a broadly applicable computational method to engineer protein dynamics that we term meta-multistate design. We used this methodology to design spontaneous exchange between two novel conformations introduced into the global fold of Streptococcal protein G domain β1. The designed proteins, named DANCERs, for dynamic and native conformational exchangers, are stably folded and switch between predicted conformational states on the millisecond timescale. The successful introduction of defined dynamics on functional timescales opens the door to new applications requiring a protein to spontaneously access multiple conformational states.

Submission Details

ID: pWSXUFP43

Submitter: Roberto Chica

Submission Date: Dec. 19, 2017, 10:55 a.m.

Version: 2

Publication Details
Davey JA;Damry AM;Goto NK;Chica RA,Nat Chem Biol (2017) Rational design of proteins that exchange on functional timescales. PMID:29058725
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
1EM7 2000-03-16T00:00:00+0000 2.0 HELIX VARIANT OF THE B1 DOMAIN FROM STREPTOCOCCAL PROTEIN G
1GB1 1991-05-15T00:00:00+0000 0 A NOVEL, HIGHLY STABLE FOLD OF THE IMMUNOGLOBULIN BINDING DOMAIN OF STREPTOCOCCAL PROTEIN G
1IGC 1994-08-05T00:00:00+0000 2.6 IGG1 FAB FRAGMENT (MOPC21) COMPLEX WITH DOMAIN III OF PROTEIN G FROM STREPTOCOCCUS
1IGD 1994-08-05T00:00:00+0000 1.1 THE THIRD IGG-BINDING DOMAIN FROM STREPTOCOCCAL PROTEIN G: AN ANALYSIS BY X-RAY CRYSTALLOGRAPHY OF THE STRUCTURE ALONE AND IN A COMPLEX WITH FAB
1LE3 2002-04-09T00:00:00+0000 0 NMR Structure of Tryptophan Zipper 4: A Stable Beta-Hairpin Peptide Based on the C-terminal Hairpin of the B1 Domain of Protein G
1MPE 2002-09-12T00:00:00+0000 0 Ensemble of 20 structures of the tetrameric mutant of the B1 domain of streptococcal protein G
1MVK 2002-09-25T00:00:00+0000 2.5 X-ray structure of the tetrameric mutant of the B1 domain of streptococcal protein G
1PGA 1993-11-23T00:00:00+0000 2.07 TWO CRYSTAL STRUCTURES OF THE B1 IMMUNOGLOBULIN-BINDING DOMAIN OF STREPTOCOCCAL PROTEIN G AND COMPARISON WITH NMR
1PGB 1993-11-23T00:00:00+0000 1.92 TWO CRYSTAL STRUCTURES OF THE B1 IMMUNOGLOBULIN-BINDING DOMAIN OF STREPTOCCOCAL PROTEIN G AND COMPARISON WITH NMR
1PGX 1992-04-03T00:00:00+0000 1.66 THE 1.66 ANGSTROMS X-RAY STRUCTURE OF THE B2 IMMUNOGLOBULIN-BINDING DOMAIN OF STREPTOCOCCAL PROTEIN G AND COMPARISON TO THE NMR STRUCTURE OF THE B1 DOMAIN

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
100.0 Immunoglobulin G-binding protein G P19909 SPG2_STRSG
100.0 Immunoglobulin G-binding protein G P06654 SPG1_STRSG