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Crystal structure of complement protein C8gamma in complex with a peptide containing the C8gamma binding site on C8alpha: implications for C8gamma ligand binding.

Lovelace LL, Chiswell B, Slade DJ, Sodetz JM, Lebioda L
Mol Immunol 45 750-6 (2008)
Cited: 15 times
EuropePMC logo PMID: 17692377

Abstract

Human C8 is one of five complement components (C5b, C6, C7, C8 and C9) that interact to form the cytolytic membrane attack complex. It contains three genetically distinct subunits; C8alpha and C8gamma form a disulfide-linked C8alpha-gamma heterodimer that is noncovalently associated with C8beta. The C8alpha subunit is homologous to C8beta, C6, C7 and C9 and together they form the MAC family of proteins. By contrast, C8gamma is the only lipocalin in the complement system. Like other lipocalins, it has a core beta-barrel structure forming a calyx with a distinct binding pocket for a small and as yet unidentified ligand. The binding site on C8alpha for C8gamma was previously localized to a 19-residue segment which contains an insertion (indel) that is unique to C8alpha. Included in the indel is C8alpha Cys 164 which links to Cys 40 in C8gamma. In the present study, C8gamma containing a C40A substitution was co-crystallized with a synthetic indel peptide containing the equivalent of a C8alpha C164A substitution. The X-ray crystal structure shows that the indel peptide completely fills the upper portion of the putative C8gamma ligand binding pocket and is in contact with all four loops at the calyx entrance. The lower part of the C8gamma cavity is either unoccupied or contains disordered solvent. The validity of the structure is supported by the spatial arrangement of C8alpha Ala 164 in the peptide and C8gamma Ala 40, which are within disulfide-bonding distance of each other. Corresponding studies in solution indicate the C8gamma ligand binding site is also occupied by the indel segment of C8alpha in whole C8. These results suggest a role for C8alpha in regulating access to the putative C8gamma ligand binding site.

Articles - 2qos mentioned but not cited (5)

  1. Crystal structure of the MACPF domain of human complement protein C8 alpha in complex with the C8 gamma subunit. Slade DJ, Lovelace LL, Chruszcz M, Minor W, Lebioda L, Sodetz JM. J Mol Biol 379 331-342 (2008)
  2. Benchmarking of different molecular docking methods for protein-peptide docking. Agrawal P, Singh H, Srivastava HK, Singh S, Kishore G, Raghava GPS. BMC Bioinformatics 19 426 (2019)
  3. Using parallelized incremental meta-docking can solve the conformational sampling issue when docking large ligands to proteins. Devaurs D, Antunes DA, Hall-Swan S, Mitchell N, Moll M, Lizée G, Kavraki LE. BMC Mol Cell Biol 20 42 (2019)
  4. Evidence that immunization with TP0751, a bipartite Treponema pallidum lipoprotein with an intrinsically disordered region and lipocalin fold, fails to protect in the rabbit model of experimental syphilis. Luthra A, Montezuma-Rusca JM, La Vake CJ, LeDoyt M, Delgado KN, Davenport TC, Fiel-Gan M, Caimano MJ, Radolf JD, Hawley KL. PLoS Pathog 16 e1008871 (2020)
  5. PepPro: A Nonredundant Structure Data Set for Benchmarking Peptide-Protein Computational Docking. Xu X, Zou X. J Comput Chem 41 362-369 (2020)


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  1. The 1.8-A crystal structure of alpha1-acid glycoprotein (Orosomucoid) solved by UV RIP reveals the broad drug-binding activity of this human plasma lipocalin. Schönfeld DL, Ravelli RB, Mueller U, Skerra A. J Mol Biol 384 393-405 (2008)
  2. Serendipitous fatty acid binding reveals the structural determinants for ligand recognition in apolipoprotein M. Sevvana M, Ahnström J, Egerer-Sieber C, Lange HA, Dahlbäck B, Muller YA. J Mol Biol 393 920-936 (2009)
  3. Structure of human complement C8, a precursor to membrane attack. Bubeck D, Roversi P, Donev R, Morgan BP, Llorca O, Lea SM. J Mol Biol 405 325-330 (2011)
  4. Chaperone-like activity of the acute-phase component human serum alpha 1-acid glycoprotein: inhibition of thermal- and chemical-induced aggregation of various proteins. Zsila F. Bioorg Med Chem Lett 20 1205-1209 (2010)
  5. Molecular cloning of the alpha subunit of complement component C8 (CpC8α) of whitespotted bamboo shark (Chiloscyllium plagiosum). Wang Y, Zhang M, Wang C, Ye B, Hua Z. Fish Shellfish Immunol 35 1993-2000 (2013)
  6. A disulfide linked model of the complement protein C8gamma complexed with C8alpha indel peptide. Stavrakoudis A. J Mol Model 15 165-171 (2009)
  7. The crystal structure of human protein α1M reveals a chromophore-binding site and two putative protein-protein interfaces. Zhang Y, Gao Z, Guo Z, Zhang H, Zhang Z, Luo M, Hou H, Huang A, Dong Y, Wang D. Biochem Biophys Res Commun 439 346-350 (2013)


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