Stabilization of bound polycyclic aromatic hydrocarbons by a π-cation interaction

Pellequer, Jean‐Luc; Zhao, Bailin; Kao, Hui-I.; Bell, Christopher W.; Li, Kai; Li, Qing X.; Karu, Alexander E.; Roberts, Victoria A.

doi:10.1006/jmbi.2000.4033

Cited by 39 publications

(35 citation statements)

References 44 publications

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“…Short side chains at L34 and L89, which are also present in the esterolytic antibodies 48G7 and CNJ206 (Table 5), are important for creating the deep pocket. The PCB phenyl ring contacts the guanidinium group of ArgL46, creating a -cation interaction in which this cationic side chain may stabilize the bound aromatic ligand, as we found in antibody binding of polycyclic aromatic hydrocarbons (Pellequer et al, 2000). The side chains of residues TyrL91, TyrL96, SerH95 and Trp H98 create the narrowing at the top of the deep pocket.…”

Section: Interactions Of S2b1 With Bound Pcb77mentioning

confidence: 88%

“…We built a cis-peptide bond between TrpH98 and ProH99, as is present in AN02, to give model B of S2B1. Finally, models A and B were energyminimized with the X-PLOR program (Brünger, 1992) using parameters from the all-atom force field (MacKerell et al, 1998), as previously described (Pellequer et al, 2000). Docking PCBs to S2B1 by energy minimization PCB77 was first docked to S2B1 models A and B manually, using computer graphics.…”

Section: Construction Of the S2b1 Fvmentioning

confidence: 99%

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Structural basis for preferential binding of non-ortho-substituted polychlorinated biphenyls by the monoclonal antibody S2B1

et al. 2005

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Polychlorinated biphenyls (PCBs) are a family of 209 isomers (congeners) with a wide range of toxic effects. In structural terms, they are of two types: those with and those without chlorines at the ortho positions (2, 2', 6 and 6'). Only 20 congeners have no ortho chlorines. Three of these are bound by the aryl hydrocarbon receptor and are one to four orders of magnitude more toxic than all others. A monoclonal antibody, S2B1, and its recombinant Fab have high selectivity and nanomolar binding affinities for two of the most toxic non-ortho-chlorinated PCBs, 3,4,3',4'-tetrachlorobiphenyl and 3,4,3',4',5'-pentachlorobiphenyl. To investigate the basis for these properties, we built a three-dimensional structure model of the S2B1 variable fragment (Fv) based on the high-resolution crystallographic structures of antibodies 48G7 and N1G9. Two plausible conformations for the complementarity-determining region (CDR) H3 loop led to two putative PCB-binding pockets with very different shapes (models A and B). Docking studies using molecular mechanics and potentials of mean force (PMF) indicated that model B was most consistent with the selectivity observed for S2B1 in competition ELISAs. The binding site in model B had a deep, narrow pocket between V(L) and V(H), with a slight constriction at the top that opened into a wider pocket between CDRs H1 and H3 on the antibody surface. This binding site resembles those of esterolytic antibodies that bind haptens with phenyl rings. One phenyl ring of the PCB fits into the deep pocket, and the other ring is bound in the shallower one. The bound PCB is surrounded by the side chains of TyrL91, TyrL96 and TrpH98, and it has a pi-cation interaction with ArgL46. The tight fit of the binding pocket around the ortho positions of the bound PCBs indicates that steric hindrance of ortho chlorines in the binding site, rather than induced conformational change of the PCBs, is responsible for the selectivity of S2B1.

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Section: Interactions Of S2b1 With Bound Pcb77mentioning

confidence: 88%

Section: Construction Of the S2b1 Fvmentioning

confidence: 99%

Structural basis for preferential binding of non-ortho-substituted polychlorinated biphenyls by the monoclonal antibody S2B1

et al. 2005

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“…A comparative modeling technique was used to build a three-dimensional model of the recombinant variable fragment of Mab U08S (Pellequer et al, 2000;Pellequer et al, 2005). Due to the strong similarity between Mab U04S and Mab U08S, the same antibody template was used (PDB code 1AY1) (Murali et al, 1998).…”

Section: Kinetic Analysismentioning

confidence: 99%

On molecular recognition of an uranyl chelate by monoclonal antibodies

Teulon

Odorico

Chen

et al. 2007

J of Molecular Recognition

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The energy landscape of the uranyl (UO2) chelate dissociated from a monoclonal antibody U08S was investigated using dynamic force spectroscopy (DFS). The uranyl ion (UO2(2+)) is chelated with the ligand dicarboxy-phenanthroline (DCP). The monoclonal antibody U08S was raised against UO2-DCP and does not cross-react with DCP alone. The results of plotting the most probable force against the logarithm of the loading rate show two distinguished values of slopes of multiple fitting lines, as observed in our previous study on that system with monoclonal antibody U04S (Odorico et al., 2007a. Biophys. J. 93: 645-654.). It indicates an unbinding process undergoing at least two activation states. We have generated the histogram of unbinding events with respect to the composite stiffness of the complex between the protein and the uranyl compound. Combining the model of Bell and Evans with that of Williams, we have estimated the number of parallel bonds involved in the unbinding process and determined the value of stiffness for individual bonds. We propose that the uranyl compound binds to the two antibodies U04S and U0c at structurally equivalent locations and forms the interaction with similar coordination modes. In addition, the unbinding process goes through two steps; the first weakens the bonding of the central metal with AspL50 of the antibody and the second breaks other non-bonded interactions of the compound with the antibody.

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“…As a general rule proteins can use aromatic side-chains to stabilize bound cationic ligands. However, recently the reciprocal process in which a cationic protein side-chain stabilizes a neutral aromatic ligand has been demonstrated [Pellequer et al, 2000]. Moreover, now there is strong evidence that in the platelet ®brinogen receptor, gpIIbgIIIa, p-electrons may substitute for the carboxyl group present in other RGD-types of ligands [Thorpe et al, 1999].…”

Section: Discussionmentioning

confidence: 98%

Non‐natural CBP2 binding peptides and peptomers modulate carcinoma cell adhesion and invasion

Hebert

Coletta

Norris

et al. 2001

J of Cellular Biochemistry

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A combinatorial approach that utilized a repertoire of bacteriophage-peptides has identified a number of non-natural CBP2 binding peptides. Moreover, co-localization of some of these peptides with CBP2 in a number of tumor cell lines demonstrated that the peptides were directed to an intracellular location spatially coincident with the normal distribution of CBP2 [Sauk et al., 2000]. From among these sequences WHYPWFQNWAMA and LDSRYSLQAAMY were the most effective CBP2 binding peptides and best fulfilled the combinatorial motif containing deep hydrophobic pockets. When the hydropathic profiles of collagen alpha1(IV) and alpha2 (IV) were compared with these dodecapeptides, the hydropathic profiles of WHYPWFQNWAMA and LDSRYSLQAAMY closely matched those of alpha1(IV) 414-452 and alpha1(IV)531-543. These peptides were shown to be functional peptidomimics and possessed the ability to alter cell adhesion and invasion of human squamous cell carcinoma cell lines. Peptomers were formed of these non-natural peptides to explore the role that a repetitive peptide may have on cell adhesion. The enhanced cell adhesion observed with the peptomers required both CBP2 antibodies and integrin antibodies for inhibition. The enhanced adhesion observed even in the face of combined antibody inhibition was consistent with such complexes possessing correspondingly slower dissociation rates. Thus, suggesting that peptomers may function in a like manner to multimeric peptide MHC complexes (tetramers) binding more than one cell receptor on a specific cell. These findings evoke both peptidomimics of native ligands and their peptomers as potential reagents by which to target tumor cells for chemotherapy, imaging, or retargeting viral vectors for gene therapy.

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Stabilization of bound polycyclic aromatic hydrocarbons by a π-cation interaction

Cited by 39 publications

References 44 publications

Structural basis for preferential binding of non-ortho-substituted polychlorinated biphenyls by the monoclonal antibody S2B1

Structural basis for preferential binding of non-ortho-substituted polychlorinated biphenyls by the monoclonal antibody S2B1

On molecular recognition of an uranyl chelate by monoclonal antibodies

Non‐natural CBP2 binding peptides and peptomers modulate carcinoma cell adhesion and invasion

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