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Structure of human histocompatibility leukocyte antigen (HLA)-Cw4, a ligand for the KIR2D natural killer cell inhibitory receptor.

Fan QR, Wiley DC - J. Exp. Med. (1999)

Bottom Line: The structure reveals an unusual pattern of internal hydrogen bonding among peptide residues.The peptide is anchored in four specificity pockets in the cleft and secured by extensive hydrogen bonds between the peptide main chain and the cleft.The surface of HLA-Cw4 has electrostatic complementarity to the surface of the NK cell inhibitory receptor KIR2D.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts 02138, USA.

ABSTRACT
The crystal structure of the human class I major histocompatibility complex molecule, human histocompatibility leukocyte antigen (HLA)-Cw4, the ligand for a natural killer (NK) cell inhibitory receptor, has been determined, complexed with a nonameric consensus peptide (QYDDAVYKL). Relative to HLA-A2, the peptide binding groove is widened around the COOH terminus of the alpha 1 helix, which contains residues that determine the specificity of HLA-Cw4 for the inhibitory NK receptor, KIR2D. The structure reveals an unusual pattern of internal hydrogen bonding among peptide residues. The peptide is anchored in four specificity pockets in the cleft and secured by extensive hydrogen bonds between the peptide main chain and the cleft. The surface of HLA-Cw4 has electrostatic complementarity to the surface of the NK cell inhibitory receptor KIR2D.

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(a) Stereo diagram of the hydrogen bonds formed between the peptide and HLA-Cw4 cleft (RIBBONS; reference 69). Conserved hydrogen bonds are represented by black dashed lines, and the other hydrogen bonds are in light gray. The residues from HLA-Cw4 are colored dark gray. The peptide is in yellow. (b) Internal hydrogen bonds formed within HLA-Cw4–bound peptide.
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Figure 3: (a) Stereo diagram of the hydrogen bonds formed between the peptide and HLA-Cw4 cleft (RIBBONS; reference 69). Conserved hydrogen bonds are represented by black dashed lines, and the other hydrogen bonds are in light gray. The residues from HLA-Cw4 are colored dark gray. The peptide is in yellow. (b) Internal hydrogen bonds formed within HLA-Cw4–bound peptide.

Mentions: Structures of HLA-A and -B have demonstrated that the ends of the peptides (P1–P2, P8–P9) are similarly bound in the cleft through conserved hydrogen bonds, whereas the structural variations occur in the central portion of the peptides. Fig. 2 c compares the conformation of peptides bound to HLA-Cw4 (QYDDAVYKL), HLA-A2 (Tax peptide, LLFGYPVYV; reference 32), and HLA-B53 (epitope gag peptide from HIV2, TPYDINQML; reference 33). As in other HLA structures, the peptide termini in HLA-Cw4 are anchored in the cleft by a number of contacts between the peptide main chain atoms and conserved MHC side chains (Table ; Fig. 3 a). At the NH2 terminus, the P1Gln main chain atoms hydrogen-bond to three tyrosine residues from HLA-Cw4 (Tyr7, 159, and 171). A hydrogen bond between the main chain NH2 group of P2Tyr and the side chain carboxylate of Glu63, which is observed in HLA-A2 and -B27 but absent in HLA-B53, is found in the HLA-Cw4 structure. The conserved hydrogen bonds at the COOH terminus include the ones from the terminal carboxylate oxygen of P9Leu to the side chains of Thr143 and Lys146. The invariant hydrogen bond from the carbonyl oxygen at P8Lys to the pyrrole nitrogen of Trp147 is also present. In addition to the conserved hydrogen bonding network found at the peptide termini, extensive interactions also occur between HLA-Cw4 and the central portion of the peptide. For peptide residues P2–P8, there are five hydrogen bonds from the peptide main chain to HLA-Cw4 side chain atoms and two from the peptide side chain to HLA-Cw4 side chain atoms. We have not been able to observe any water molecule in the region of the peptide, probably due to the limitation of the resolution.


Structure of human histocompatibility leukocyte antigen (HLA)-Cw4, a ligand for the KIR2D natural killer cell inhibitory receptor.

Fan QR, Wiley DC - J. Exp. Med. (1999)

(a) Stereo diagram of the hydrogen bonds formed between the peptide and HLA-Cw4 cleft (RIBBONS; reference 69). Conserved hydrogen bonds are represented by black dashed lines, and the other hydrogen bonds are in light gray. The residues from HLA-Cw4 are colored dark gray. The peptide is in yellow. (b) Internal hydrogen bonds formed within HLA-Cw4–bound peptide.
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Related In: Results  -  Collection

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Figure 3: (a) Stereo diagram of the hydrogen bonds formed between the peptide and HLA-Cw4 cleft (RIBBONS; reference 69). Conserved hydrogen bonds are represented by black dashed lines, and the other hydrogen bonds are in light gray. The residues from HLA-Cw4 are colored dark gray. The peptide is in yellow. (b) Internal hydrogen bonds formed within HLA-Cw4–bound peptide.
Mentions: Structures of HLA-A and -B have demonstrated that the ends of the peptides (P1–P2, P8–P9) are similarly bound in the cleft through conserved hydrogen bonds, whereas the structural variations occur in the central portion of the peptides. Fig. 2 c compares the conformation of peptides bound to HLA-Cw4 (QYDDAVYKL), HLA-A2 (Tax peptide, LLFGYPVYV; reference 32), and HLA-B53 (epitope gag peptide from HIV2, TPYDINQML; reference 33). As in other HLA structures, the peptide termini in HLA-Cw4 are anchored in the cleft by a number of contacts between the peptide main chain atoms and conserved MHC side chains (Table ; Fig. 3 a). At the NH2 terminus, the P1Gln main chain atoms hydrogen-bond to three tyrosine residues from HLA-Cw4 (Tyr7, 159, and 171). A hydrogen bond between the main chain NH2 group of P2Tyr and the side chain carboxylate of Glu63, which is observed in HLA-A2 and -B27 but absent in HLA-B53, is found in the HLA-Cw4 structure. The conserved hydrogen bonds at the COOH terminus include the ones from the terminal carboxylate oxygen of P9Leu to the side chains of Thr143 and Lys146. The invariant hydrogen bond from the carbonyl oxygen at P8Lys to the pyrrole nitrogen of Trp147 is also present. In addition to the conserved hydrogen bonding network found at the peptide termini, extensive interactions also occur between HLA-Cw4 and the central portion of the peptide. For peptide residues P2–P8, there are five hydrogen bonds from the peptide main chain to HLA-Cw4 side chain atoms and two from the peptide side chain to HLA-Cw4 side chain atoms. We have not been able to observe any water molecule in the region of the peptide, probably due to the limitation of the resolution.

Bottom Line: The structure reveals an unusual pattern of internal hydrogen bonding among peptide residues.The peptide is anchored in four specificity pockets in the cleft and secured by extensive hydrogen bonds between the peptide main chain and the cleft.The surface of HLA-Cw4 has electrostatic complementarity to the surface of the NK cell inhibitory receptor KIR2D.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts 02138, USA.

ABSTRACT
The crystal structure of the human class I major histocompatibility complex molecule, human histocompatibility leukocyte antigen (HLA)-Cw4, the ligand for a natural killer (NK) cell inhibitory receptor, has been determined, complexed with a nonameric consensus peptide (QYDDAVYKL). Relative to HLA-A2, the peptide binding groove is widened around the COOH terminus of the alpha 1 helix, which contains residues that determine the specificity of HLA-Cw4 for the inhibitory NK receptor, KIR2D. The structure reveals an unusual pattern of internal hydrogen bonding among peptide residues. The peptide is anchored in four specificity pockets in the cleft and secured by extensive hydrogen bonds between the peptide main chain and the cleft. The surface of HLA-Cw4 has electrostatic complementarity to the surface of the NK cell inhibitory receptor KIR2D.

Show MeSH