Dataset Information

The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human ?V?3 Integrin via Steric Hindrance.

ABSTRACT: The LM609 antibody specifically recognizes ?V?3 integrin and inhibits angiogenesis, bone resorption, and viral infections in an arginine-glycine-aspartate-independent manner. LM609 entered phase II clinical trials for the treatment of several cancers and was also used for ?V?3-targeted radioimmunotherapy. To elucidate the mechanisms of recognition and inhibition of ?V?3 integrin, we solved the structure of the LM609 antigen-binding fragment by X-ray crystallography and determined its binding affinity for ?V?3. Using single-particle electron microscopy, we show that LM609 binds at the interface between the ?-propeller domain of the ?V chain and the ?I domain of the ?3 chain, near the RGD-binding site, of all observed integrin conformational states. Integrating these data with fluorescence size-exclusion chromatography, we demonstrate that LM609 sterically hinders access of large ligands to the RGD-binding pocket, without obstructing it. This work provides a structural framework to expedite future efforts utilizing LM609 as a diagnostic or therapeutic tool.

SUBMITTER: Borst AJ

PROVIDER: S-EPMC5689087 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human αVβ3 Integrin via Steric Hindrance.

Borst Andrew J AJ James Zachary M ZM Zagotta William N WN Ginsberg Mark M Rey Felix A FA DiMaio Frank F Backovic Marija M Veesler David D

Structure (London, England : 1993) 20171012 11

The LM609 antibody specifically recognizes αVβ3 integrin and inhibits angiogenesis, bone resorption, and viral infections in an arginine-glycine-aspartate-independent manner. LM609 entered phase II clinical trials for the treatment of several cancers and was also used for αVβ3-targeted radioimmunotherapy. To elucidate the mechanisms of recognition and inhibition of αVβ3 integrin, we solved the structure of the LM609 antigen-bindin ...[more]

PMID: 29033288

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Project description:BackgroundIn computational structural biology, structure comparison is fundamental for our understanding of proteins. Structure comparison is, e.g., algorithmically the starting point for computational studies of structural evolution and it guides our efforts to predict protein structures from their amino acid sequences. Most methods for structural alignment of protein structures optimize the distances between aligned and superimposed residue pairs, i.e., the distances traveled by the aligned and superimposed residues during linear interpolation. Considering such a linear interpolation, these methods do not differentiate if there is room for the interpolation, if it causes steric clashes, or more severely, if it changes the topology of the compared protein backbone curves.ResultsTo distinguish such cases, we analyze the linear interpolation between two aligned and superimposed backbones. We quantify the amount of steric clashes and find all self-intersections in a linear backbone interpolation. To determine if the self-intersections alter the protein's backbone curve significantly or not, we present a path-finding algorithm that checks if there exists a self-avoiding path in a neighborhood of the linear interpolation. A new path is constructed by altering the linear interpolation using a novel interpretation of Reidemeister moves from knot theory working on three-dimensional curves rather than on knot diagrams. Either the algorithm finds a self-avoiding path or it returns a smallest set of essential self-intersections. Each of these indicates a significant difference between the folds of the aligned protein structures. As expected, we find at least one essential self-intersection separating most unknotted structures from a knotted structure, and we find even larger motions in proteins connected by obstruction free linear interpolations. We also find examples of homologous proteins that are differently threaded, and we find many distinct folds connected by longer but simple deformations. TM-align is one of the most restrictive alignment programs. With standard parameters, it only aligns residues superimposed within 5 Ångström distance. We find 42165 topological obstructions between aligned parts in 142068 TM-alignments. Thus, this restrictive alignment procedure still allows topological dissimilarity of the aligned parts.ConclusionsBased on the data we conclude that our program ProteinAlignmentObstruction provides significant additional information to alignment scores based solely on distances between aligned and superimposed residue pairs.

Dataset Information

The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human ?V?3 Integrin via Steric Hindrance.

Publications

The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human α<sub>V</sub>β<sub>3</sub> Integrin via Steric Hindrance.

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