scholarly journals The crystal structure of avian CD1 reveals a smaller, more primordial antigen-binding pocket compared to mammalian CD1

2008 ◽  
Vol 105 (46) ◽  
pp. 17925-17930 ◽  
Author(s):  
Dirk M. Zajonc ◽  
Harald Striegl ◽  
Christopher C. Dascher ◽  
Ian A. Wilson
Keyword(s):  
Crystal Structure ◽  
Binding Pocket ◽  
Antigen Binding ◽  
Single Chain ◽  
Antigen Binding Site ◽  
Ligand Interaction ◽  
Hydrogen Bond Interactions ◽  
Hydrophobic Binding ◽  
Mhc Locus ◽  
Binding Groove

The molecular details of glycolipid presentation by CD1 antigen-presenting molecules are well studied in mammalian systems. However, little is known about how these non-classical MHC class I (MHCI) molecules diverged from the MHC locus to create a more complex, hydrophobic binding groove that binds lipids rather than peptides. To address this fundamental question, we have determined the crystal structure of an avian CD1 (chCD1–2) that shares common ancestry with mammalian CD1 from ≈310 million years ago. The chCD1–2 antigen-binding site consists of a compact, narrow, central hydrophobic groove or pore rather than the more open, 2-pocket architecture observed in mammalian CD1s. Potential antigens then would be restricted in size to single-chain lipids or glycolipids. An endogenous ligand, possibly palmitic acid, serves to illuminate the mode and mechanism of ligand interaction with chCD1–2. The palmitate alkyl chain is inserted into the relatively shallow hydrophobic pore; its carboxyl group emerges at the receptor surface and is stabilized by electrostatic and hydrogen bond interactions with an arginine residue that is conserved in all known CD1 proteins. In addition, other novel features, such as an A′ loop that interrupts and segments the normally long, continuous α1 helix, are unique to chCD1–2 and contribute to the unusually narrow binding groove, thereby limiting its size. Because birds and mammals share a common ancestor, but the rate of evolution is slower in birds than in mammals, the chCD1–2-binding groove probably represents a more primordial CD1-binding groove.

Humanization of a highly stable single-chain antibody by structure-based antigen-binding site grafting

2008 ◽  
Vol 45 (9) ◽  
pp. 2474-2485 ◽  
Author(s):  
Maria Elena Villani ◽  
Veronica Morea ◽  
Valerio Consalvi ◽  
Roberta Chiaraluce ◽  
Angiola Desiderio ◽  
...  
Keyword(s):  
Binding Site ◽  
Antigen Binding ◽  
Single Chain ◽  
Single Chain Antibody ◽  
Antigen Binding Site

scholarly journals Kappa-on-Heavy (KoH) bodies are a distinct class of fully-human antibody-like therapeutic agents with antigen-binding properties

2019 ◽  
Vol 117 (1) ◽  
pp. 292-299 ◽  
Author(s):  
Lynn E. Macdonald ◽  
Karoline A. Meagher ◽  
Matthew C. Franklin ◽  
Natasha Levenkova ◽  
Johanna Hansen ◽  
...  
Keyword(s):  
Small Molecules ◽  
Binding Pocket ◽  
Human Antibody ◽  
Antigen Binding ◽  
Wild Type ◽  
Antigen Binding Site ◽  
Binding Properties ◽  
Variable Domains ◽  
Constant Domains ◽  
Ig Heavy Chain

We describe a Kappa-on-Heavy (KoH) mouse that produces a class of highly diverse, fully human, antibody-like agents. This mouse was made by replacing the germline variable sequences of both the Ig heavy-chain (IgH) and Ig kappa (IgK) loci with the human IgK germline variable sequences, producing antibody-like molecules with an antigen binding site made up of 2 kappa variable domains. These molecules, named KoH bodies, structurally mimic naturally existing Bence-Jones light-chain dimers in their variable domains and remain wild-type in their antibody constant domains. Unlike artificially diversified, nonimmunoglobulin alternative scaffolds (e.g., DARPins), KoH bodies consist of a configuration of normal Ig scaffolds that undergo natural diversification in B cells. Monoclonal KoH bodies have properties similar to those of conventional antibodies but exhibit an enhanced ability to bind small molecules such as the endogenous cardiotonic steroid marinobufagenin (MBG) and nicotine. A comparison of crystal structures of MBG bound to a KoH Fab versus a conventional Fab showed that the KoH body has a much deeper binding pocket, allowing MBG to be held 4 Å further down into the combining site between the 2 variable domains.

scholarly journals High-Resolution Crystal Structure of the Subclass B3 Metallo-β-Lactamase BJP-1: Rational Basis for Substrate Specificity and Interaction with Sulfonamides

2010 ◽  
Vol 54 (10) ◽  
pp. 4343-4351 ◽  
Author(s):  
Jean-Denis Docquier ◽  
Manuela Benvenuti ◽  
Vito Calderone ◽  
Magdalena Stoczko ◽  
Nicola Menciassi ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Active Site ◽  
Bradyrhizobium Japonicum ◽  
Active Sites ◽  
Structural Diversity ◽  
Binding Pocket ◽  
Structural Basis ◽  
Side Chain ◽  
Functional Heterogeneity ◽  
Hydrophobic Binding

ABSTRACT Metallo-β-lactamases (MBLs) are important enzymatic factors in resistance to β-lactam antibiotics that show important structural and functional heterogeneity. BJP-1 is a subclass B3 MBL determinant produced by Bradyrhizobium japonicum that exhibits interesting properties. BJP-1, like CAU-1 of Caulobacter vibrioides, overall poorly recognizes β-lactam substrates and shows an unusual substrate profile compared to other MBLs. In order to understand the structural basis of these properties, the crystal structure of BJP-1 was obtained at 1.4-Å resolution. This revealed significant differences in the conformation and locations of the active-site loops, determining a rather narrow active site and the presence of a unique N-terminal helix bearing Phe-31, whose side chain binds in the active site and represents an obstacle for β-lactam substrate binding. In order to probe the potential of sulfonamides (known to inhibit various zinc-dependent enzymes) to bind in the active sites of MBLs, the structure of BJP-1 in complex with 4-nitrobenzenesulfonamide was also obtained (at 1.33-Å resolution), thereby revealing the mode of interaction of these molecules in MBLs. Interestingly, sulfonamide binding resulted in the displacement of the side chain of Phe-31 from its hydrophobic binding pocket, where the benzene ring of the molecule is now found. These data further highlight the structural diversity shown by MBLs but also provide interesting insights in the structure-function relationships of these enzymes. More importantly, we provided the first structural observation of MBL interaction with sulfonamides, which might represent an interesting scaffold for the design of MBL inhibitors.

The molecular structure of the μ‎-opioid receptor

2018 ◽  
Author(s):  
Roger D. Knaggs
Keyword(s):  
Crystal Structure ◽  
Side Effects ◽  
Opioid Receptor ◽  
Three Dimensional ◽  
Binding Pocket ◽  
Dimensional Structure ◽  
Ligand Interaction ◽  
Analgesic Effects ◽  
Interaction Sites ◽  
Potential Ligand

The landmark paper discussed in this chapter describes the crystal structure of the μ‎-opioid receptor (also known as MOP-1). Opioids are some of the oldest known drugs and have been used for over 4,000 years; however, in addition to having beneficial analgesic effects, they are associated with a myriad of side effects that can minimize their use. Although the gene sequences of the opioid receptors were determined in the 1990s it has taken much longer to translate this into visualizing their three-dimensional structure. The μ‎-opioid receptor consists of seven transmembrane α‎-helices that are connected by three extracellular loops and three intracellular loops, with a wide open binding pocket which offers many potential ligand interaction sites, and evidence of dimerization. Understanding the crystal structure of the μ‎-opioid receptor in much more detail aids explanation of the molecular determinants of ligand recognition and selectivity and will be of use in designing novel opioids with improved efficacy and fewer side effects.

scholarly journals Structure of the Anti-C60 Fullerene Antibody Fab Fragment: Structural Determinants of Fullerene Binding

Acta Naturae ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 58-65 ◽  
Author(s):  
E. M. Osipov ◽  
O. D. Hendrickson ◽  
T. V. Tikhonova ◽  
A. V. Zherdev ◽  
O. N. Solopova ◽  
...  
Keyword(s):  
Binding Site ◽  
Hydrophobic Surface ◽  
Binding Pocket ◽  
C60 Fullerene ◽  
Antigen Binding ◽  
Structural Determinants ◽  
Antigen Binding Site ◽  
Fab Fragment ◽  
X Ray Crystallography ◽  
Solvent Accessible Area

The structure of the anti-C60 fullerene antibody Fab fragment (FabC60) was solved by X-ray crystallography. The computer-aided docking of C60 into the antigen-binding pocket of FabC60 showed that binding of C60 to FabC60 is governed by the enthalpy and entropy; namely, by - stacking interactions with aromatic residues of the antigen-binding site and reduction of the solvent-accessible area of the hydrophobic surface of C60. A fragment of the mobile CDR H3 loop located on the surface of FabC60 interferes with C60 binding in the antigen-binding site, thereby resulting in low antibody affinity for C60. The structure of apo-FabC60 has been deposited with pdbid 6H3H.

scholarly journals Crystal structure of the anti-(carcinoembryonic antigen) single-chain Fv antibody MFE-23 and a model for antigen binding based on intermolecular contacts

2000 ◽  
Vol 346 (2) ◽  
pp. 519-528 ◽  
Author(s):  
Mark K. BOEHM ◽  
Adam L. CORPER ◽  
Tommy WAN ◽  
Maninder K. SOHI ◽  
Brian J. SUTTON ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Carcinoembryonic Antigen ◽  
High Surface ◽  
Immunoglobulin Superfamily ◽  
Antigen Binding ◽  
Single Chain ◽  
Antibody Molecule ◽  
Single Chain Fv ◽  
Fv Antibody ◽  
Single Chain Fv Antibody

MFE-23 is the first single-chain Fv antibody molecule to be used in patients and is used to target colorectal cancer through its high affinity for carcinoembryonic antigen (CEA), a cell-surface member of the immunoglobulin superfamily. MFE-23 contains an N-terminal variable heavy-chain domain joined by a (Gly4Ser)3 linker to a variable light-chain (VL) domain (ĸ chain) with an 11-residue C-terminal Myc-tag. Its crystal structure was determined at 2.4 Å resolution by molecular replacement with an Rcryst of 19.0%. Five of the six antigen-binding loops, L1, L2, L3, H1 and H2, conformed to known canonical structures. The sixth loop, H3, displayed a unique structure, with a β-hairpin loop and a bifurcated apex characterized by a buried Thr residue. In the crystal lattice, two MFE-23 molecules were associated back-to-back in a manner not seen before. The antigen-binding site displayed a large acidic region located mainly within the H2 loop and a large hydrophobic region within the H3 loop. Even though this structure is unliganded within the crystal, there is an unusually large region of contact between the H1, H2 and H3 loops and the β-sheet of the VL domain of an adjacent molecule (strands DEBA) as a result of intermolecular packing. These interactions exhibited remarkably high surface and electrostatic complementarity. Of seven MFE-23 residues predicted to make contact with antigen, five participated in these lattice contacts, and this model for antigen binding is consistent with previously reported site-specific mutagenesis of MFE-23 and its effect on CEA binding.

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