Journal article
Kinetic and structural analysis of mutant CD4 receptors that are defective in HIV gp120 binding
Proceedings of the National Academy of Sciences - PNAS, v 93(26), pp 15030-15035
24 Dec 1996
PMID: 8986758
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Abstract
The T-cell antigen coreceptor CD4 also serves as the receptor for
the envelope glycoprotein gp120 of HIV. Extensive mutational analysis
of CD4 has implicated residues from a portion of the extracellular
amino-terminal domain (D1) in gp120 binding. However, none of these
proteins has been fully characterized biophysically, and thus the
precise effects on molecular structure and binding interactions are
unknown. In the present study, we produced soluble versions of three
mutant CD4 molecules (F43V, G47S, and A55F) and characterized their
structural properties, thermostability, and ability to bind gp120.
Crystallographic and thermodynamic analysis showed minimal structural
alterations in the F43V and G47S mutant proteins, which have
solvent-exposed mutant side chains. In contrast, some degree of
disorder appears to exist in the folded state of A55F, as a result of
mutating a buried side chain. Real time kinetic measurements of the
interaction of the mutant proteins with gp120 showed affinity decreases
of 5-fold for G47S, 50-fold for A55F, and 200-fold for F43V. Although
both rate constants for the binding reaction were affected by these
mutations, the loss in affinity was mainly due to a decrease in on
rates, with less drastic changes occurring in the off rates. These
observations suggest the involvement of conformational adaptation in
the CD4–gp120 interaction. Together, the structural and kinetic data
confirm that F43V is a critical residue in gp120 recognition site,
which may also include main chain interactions at residue Gly-47.
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Details
- Title
- Kinetic and structural analysis of mutant CD4 receptors that are defective in HIV gp120 binding
- Creators
- Hao Wu - Department of Biochemistry and Molecular Biophysics andDavid G Myszka - Department of Biochemistry and Molecular Biophysics andSusan W Tendian - Department of Biochemistry and Molecular Biophysics andChristie G Brouillette - Department of Biochemistry and Molecular Biophysics andRay W Sweet - Department of Biochemistry and Molecular Biophysics andIrwin M Chaiken - Department of Biochemistry and Molecular Biophysics andWayne A Hendrickson - Department of Biochemistry and Molecular Biophysics and
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, v 93(26), pp 15030-15035
- Publisher
- The National Academy of Sciences of the USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:A1996WC20400009
- Scopus ID
- 2-s2.0-0030446301
- Other Identifier
- 991014877816204721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology