Abstract/Details

Ligand recognition in mutant proteins


1999 1999

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Abstract (summary)

Protein recognition events are ubiquitous processes. This thesis work focuses on two proteins and their interactions with ligands, complexes of TNF-[special characters omitted] and TNF mutants with receptor and complexes of HIV-1 protease drug resistant mutants with inhibitor. To investigate TNF's mode of binding to receptor and molecular models have been built of the complexes of TNF-[special characters omitted] with receptors R1 and R2 based on the crystal structures of TNF-[special characters omitted] and of lymphotoxin bound to R1. Analysis of differences in the model complexes showed good agreement with experimental data on the differential binding of TNF mutants to its two receptors. As a validation of modeling methods used, homology models were built and submitted as part of the CASP2 structure prediction experiment (comparative modeling targets 1, 3, 9 and 17). The prediction of target 17 (85% sequence identity) had rmsd of 0.56Å on C[special characters omitted] atoms when compared with the target. Targets 1, 3 and 9 (33–46% sequence identity) had rmsd's on core C[special characters omitted] atoms of 1.49, 1.11 and 1.24Å, respectively. To further investigate the reasons of TNF differential binding, crystal structures were determined of TNF-[special characters omitted] and the R31D mutant which binds to TNF receptor R1. Model complexes of TNF with receptors R1 and R2 have been used to predict TNF-receptor interactions. Arg 31 of wild type TNF is predicted to form an ionic interaction with the equivalent glutamic acid in both receptors R1 and R2. Asp 31 of the TNF R31D mutant is predicted to interact differently with the two receptors. The side chain of Asp 31 in two subunits of the TNF mutant is predicted to form hydrogen bond interactions with Ser 59 or Cys 70 of R1, while it has no predicted interactions with R2. Studies to investigate drug resistance were performed with HIV-1 protease mutants R8Q, D30N, K45I, M46L, G48V, V82S, N88D, and L90M. A direct relationship was not observed between catalytic activity, inhibition, and structural stability. Multiple mechanisms, both direct and indirect, are likely responsible for the observations.

Indexing (details)


Subject
Biophysics;
Molecular biology
Classification
0786: Biophysics
0307: Molecular biology
Identifier / keyword
Biological sciences, Ligand recognition, Mutant proteins, Protein recognition
Title
Ligand recognition in mutant proteins
Author
Reed, Charles Christopher
Number of pages
162
Publication year
1999
Degree date
1999
School code
0272
Source
DAI-B 60/03, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780599227453, 0599227451
Advisor
Weber, Irene T.
University/institution
Thomas Jefferson University
University location
United States -- Pennsylvania
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
9923253
ProQuest document ID
304542940
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304542940
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