Format

Send to

Choose Destination
Nat Methods. 2013 Sep;10(9):896-902. doi: 10.1038/nmeth.2592. Epub 2013 Aug 4.

Automated identification of functional dynamic contact networks from X-ray crystallography.

Author information

1
Joint Center for Structural Genomics, Stanford Synchrotron Radiation Lightsource, Stanford, California, USA. vdbedem@slac.stanford.edu

Abstract

Protein function often depends on the exchange between conformational substates. Allosteric ligand binding or distal mutations can stabilize specific active-site conformations and consequently alter protein function. Observing alternative conformations at low levels of electron density, in addition to comparison of independently determined X-ray crystal structures, can provide mechanistic insights into conformational dynamics. Here we report a new algorithm, CONTACT, that identifies contact networks of conformationally heterogeneous residues directly from high-resolution X-ray crystallography data. Contact networks determined for Escherichia coli dihydrofolate reductase (ecDHFR) predict the observed long-range pattern of NMR chemical shift perturbations of an allosteric mutation. A comparison of contact networks in wild-type and mutant ecDHFR suggests that mutations that alter optimized contact networks of coordinated motions can impair catalytic function. CONTACT-guided mutagenesis can exploit the structure-dynamics-function relationship in protein engineering and design.

Comment in

PMID:
23913260
PMCID:
PMC3760795
DOI:
10.1038/nmeth.2592
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center