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.
journal_name
Nat Methodsjournal_title
Nature methodsauthors
van den Bedem H,Bhabha G,Yang K,Wright PE,Fraser JSdoi
10.1038/nmeth.2592subject
Has Abstractpub_date
2013-09-01 00:00:00pages
896-902issue
9eissn
1548-7091issn
1548-7105pii
nmeth.2592journal_volume
10pub_type
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