Structures of an HIV and MHC binding fragment from human CD4 as refined in two crystal lattices

Seong Eon Ryu, Alemseged Truneh, Raymond W. Sweet, Wayne A. Hendrickson

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Background: The T-cell surface glycoprotein CD4 interacts with class II molecules of the major histocompatibility complex (MHC) enhancing the signal for T-cell activation. Human CD4 also interacts, at high affinity, with the HIV envelope glycoprotein, gp120, to mediate T-cell infection by HIV. Crystal structures of amino-terminal two-domain (D1D2) fragments of human CD4, which contain the residues implicated in HIV and MHC interactions, have been reported earlier. Results: We have determined the crystal structure of a new D1D2 construct by molecular replacement from a previously described crystal structure of D1D2. This structure has more uniform lattice contacts than are in the first. This gives an improved image of domain D2, which in turn has permitted further refinement of the initial structure at 2.3 å resolution against a more complete data set. The structure of the second crystal form was also refined at 2.9 å resolution. In both models, all residues from 1 to 178 are now well defined, including the loop regions in D2. Conclusions: Similarities of the molecular structure in the two lattices suggest that the D1D2 fragment works as a unit, with segmental flexibility largely restricted to the junction between domains D2 and D3. Variability of conformation in loops, including those implicated in MHC and HIV binding, requires an 'induced fit' in these interactions. Well defined density for the exposed side chain of Phe43 in both crystals confirms a prominent role for this residue in gp120 binding.

Original languageEnglish
Pages (from-to)59-74
Number of pages16
JournalStructure
Volume2
Issue number1
DOIs
StatePublished - 1994 Jan 1

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Major Histocompatibility Complex
HIV
T-Lymphocytes
HIV Envelope Protein gp120
Membrane Glycoproteins
Molecular Structure
HIV Infections

Keywords

  • CD4-MHC interaction
  • CD4-gp120 interaction
  • T-cell co-receptor
  • X-ray structure

Cite this

Ryu, Seong Eon ; Truneh, Alemseged ; Sweet, Raymond W. ; Hendrickson, Wayne A. / Structures of an HIV and MHC binding fragment from human CD4 as refined in two crystal lattices. In: Structure. 1994 ; Vol. 2, No. 1. pp. 59-74.
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Structures of an HIV and MHC binding fragment from human CD4 as refined in two crystal lattices. / Ryu, Seong Eon; Truneh, Alemseged; Sweet, Raymond W.; Hendrickson, Wayne A.

In: Structure, Vol. 2, No. 1, 01.01.1994, p. 59-74.

Research output: Contribution to journalArticle

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T1 - Structures of an HIV and MHC binding fragment from human CD4 as refined in two crystal lattices

AU - Ryu, Seong Eon

AU - Truneh, Alemseged

AU - Sweet, Raymond W.

AU - Hendrickson, Wayne A.

PY - 1994/1/1

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N2 - Background: The T-cell surface glycoprotein CD4 interacts with class II molecules of the major histocompatibility complex (MHC) enhancing the signal for T-cell activation. Human CD4 also interacts, at high affinity, with the HIV envelope glycoprotein, gp120, to mediate T-cell infection by HIV. Crystal structures of amino-terminal two-domain (D1D2) fragments of human CD4, which contain the residues implicated in HIV and MHC interactions, have been reported earlier. Results: We have determined the crystal structure of a new D1D2 construct by molecular replacement from a previously described crystal structure of D1D2. This structure has more uniform lattice contacts than are in the first. This gives an improved image of domain D2, which in turn has permitted further refinement of the initial structure at 2.3 å resolution against a more complete data set. The structure of the second crystal form was also refined at 2.9 å resolution. In both models, all residues from 1 to 178 are now well defined, including the loop regions in D2. Conclusions: Similarities of the molecular structure in the two lattices suggest that the D1D2 fragment works as a unit, with segmental flexibility largely restricted to the junction between domains D2 and D3. Variability of conformation in loops, including those implicated in MHC and HIV binding, requires an 'induced fit' in these interactions. Well defined density for the exposed side chain of Phe43 in both crystals confirms a prominent role for this residue in gp120 binding.

AB - Background: The T-cell surface glycoprotein CD4 interacts with class II molecules of the major histocompatibility complex (MHC) enhancing the signal for T-cell activation. Human CD4 also interacts, at high affinity, with the HIV envelope glycoprotein, gp120, to mediate T-cell infection by HIV. Crystal structures of amino-terminal two-domain (D1D2) fragments of human CD4, which contain the residues implicated in HIV and MHC interactions, have been reported earlier. Results: We have determined the crystal structure of a new D1D2 construct by molecular replacement from a previously described crystal structure of D1D2. This structure has more uniform lattice contacts than are in the first. This gives an improved image of domain D2, which in turn has permitted further refinement of the initial structure at 2.3 å resolution against a more complete data set. The structure of the second crystal form was also refined at 2.9 å resolution. In both models, all residues from 1 to 178 are now well defined, including the loop regions in D2. Conclusions: Similarities of the molecular structure in the two lattices suggest that the D1D2 fragment works as a unit, with segmental flexibility largely restricted to the junction between domains D2 and D3. Variability of conformation in loops, including those implicated in MHC and HIV binding, requires an 'induced fit' in these interactions. Well defined density for the exposed side chain of Phe43 in both crystals confirms a prominent role for this residue in gp120 binding.

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