Structural basis of Lewis(b) antigen binding by the Helicobacter pylori adhesin BabA
Helicobacter pylori is a leading cause of peptic ulceration and gastric cancer worldwide. To achieve colonization of the stomach, this Gram-negative bacterium adheres to Lewis(b) (Le(b)) antigens in the gastric mucosa using its outer membrane protein BabA. Structural information for BabA has been el...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Published: |
American Association for the Advancement of Science
2015
|
| Subjects: | |
| Online Access: | https://eprints.nottingham.ac.uk/37535/ |
| _version_ | 1848795479552294912 |
|---|---|
| author | Hage, Naim Howard, Tina Phillips, Chris Brassington, Claire Overman, Ross Debreczeni, Judit Gellert, Paul Stolnik, Snow Winkler, G. Sebastiaan Falcone, Franco H. |
| author_facet | Hage, Naim Howard, Tina Phillips, Chris Brassington, Claire Overman, Ross Debreczeni, Judit Gellert, Paul Stolnik, Snow Winkler, G. Sebastiaan Falcone, Franco H. |
| author_sort | Hage, Naim |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Helicobacter pylori is a leading cause of peptic ulceration and gastric cancer worldwide. To achieve colonization of the stomach, this Gram-negative bacterium adheres to Lewis(b) (Le(b)) antigens in the gastric mucosa using its outer membrane protein BabA. Structural information for BabA has been elusive, and thus, its molecular mechanism for recognizing Le(b) antigens remains unknown. We present the crystal structure of the extracellular domain of BabA, from H. pylori strain J99, in the absence and presence of Le(b) at 2.0- and 2.1-Å resolutions, respectively. BabA is a predominantly α-helical molecule with a markedly kinked tertiary structure containing a single, shallow Le(b) binding site at its tip within a β-strand motif. No conformational change occurs in BabA upon binding of Le(b), which is characterized by low affinity under acidic [K D (dissociation constant) of ~227 μM] and neutral (K D of ~252 μM) conditions. Binding is mediated by a network of hydrogen bonds between Le(b) Fuc1, GlcNAc3, Fuc4, and Gal5 residues and a total of eight BabA amino acids (C189, G191, N194, N206, D233, S234, S244, and T246) through both carbonyl backbone and side-chain interactions. The structural model was validated through the generation of two BabA variants containing N206A and combined D233A/S244A substitutions, which result in a reduction and complete loss of binding affinity to Le(b), respectively. Knowledge of the molecular basis of Le(b) recognition by BabA provides a platform for the development of therapeutics targeted at inhibiting H. pylori adherence to the gastric mucosa. |
| first_indexed | 2025-11-14T19:32:45Z |
| format | Article |
| id | nottingham-37535 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:32:45Z |
| publishDate | 2015 |
| publisher | American Association for the Advancement of Science |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-375352020-05-04T17:15:06Z https://eprints.nottingham.ac.uk/37535/ Structural basis of Lewis(b) antigen binding by the Helicobacter pylori adhesin BabA Hage, Naim Howard, Tina Phillips, Chris Brassington, Claire Overman, Ross Debreczeni, Judit Gellert, Paul Stolnik, Snow Winkler, G. Sebastiaan Falcone, Franco H. Helicobacter pylori is a leading cause of peptic ulceration and gastric cancer worldwide. To achieve colonization of the stomach, this Gram-negative bacterium adheres to Lewis(b) (Le(b)) antigens in the gastric mucosa using its outer membrane protein BabA. Structural information for BabA has been elusive, and thus, its molecular mechanism for recognizing Le(b) antigens remains unknown. We present the crystal structure of the extracellular domain of BabA, from H. pylori strain J99, in the absence and presence of Le(b) at 2.0- and 2.1-Å resolutions, respectively. BabA is a predominantly α-helical molecule with a markedly kinked tertiary structure containing a single, shallow Le(b) binding site at its tip within a β-strand motif. No conformational change occurs in BabA upon binding of Le(b), which is characterized by low affinity under acidic [K D (dissociation constant) of ~227 μM] and neutral (K D of ~252 μM) conditions. Binding is mediated by a network of hydrogen bonds between Le(b) Fuc1, GlcNAc3, Fuc4, and Gal5 residues and a total of eight BabA amino acids (C189, G191, N194, N206, D233, S234, S244, and T246) through both carbonyl backbone and side-chain interactions. The structural model was validated through the generation of two BabA variants containing N206A and combined D233A/S244A substitutions, which result in a reduction and complete loss of binding affinity to Le(b), respectively. Knowledge of the molecular basis of Le(b) recognition by BabA provides a platform for the development of therapeutics targeted at inhibiting H. pylori adherence to the gastric mucosa. American Association for the Advancement of Science 2015-08-14 Article PeerReviewed Hage, Naim, Howard, Tina, Phillips, Chris, Brassington, Claire, Overman, Ross, Debreczeni, Judit, Gellert, Paul, Stolnik, Snow, Winkler, G. Sebastiaan and Falcone, Franco H. (2015) Structural basis of Lewis(b) antigen binding by the Helicobacter pylori adhesin BabA. Science Advances, 1 (7). e1500315/1-1500315/9. ISSN 2375-2548 Helicobacter pylori; Adhesin; BabA http://advances.sciencemag.org/content/1/7/e1500315.article-info doi:10.1126/sciadv.1500315 doi:10.1126/sciadv.1500315 |
| spellingShingle | Helicobacter pylori; Adhesin; BabA Hage, Naim Howard, Tina Phillips, Chris Brassington, Claire Overman, Ross Debreczeni, Judit Gellert, Paul Stolnik, Snow Winkler, G. Sebastiaan Falcone, Franco H. Structural basis of Lewis(b) antigen binding by the Helicobacter pylori adhesin BabA |
| title | Structural basis of Lewis(b) antigen binding by the Helicobacter pylori adhesin BabA |
| title_full | Structural basis of Lewis(b) antigen binding by the Helicobacter pylori adhesin BabA |
| title_fullStr | Structural basis of Lewis(b) antigen binding by the Helicobacter pylori adhesin BabA |
| title_full_unstemmed | Structural basis of Lewis(b) antigen binding by the Helicobacter pylori adhesin BabA |
| title_short | Structural basis of Lewis(b) antigen binding by the Helicobacter pylori adhesin BabA |
| title_sort | structural basis of lewis(b) antigen binding by the helicobacter pylori adhesin baba |
| topic | Helicobacter pylori; Adhesin; BabA |
| url | https://eprints.nottingham.ac.uk/37535/ https://eprints.nottingham.ac.uk/37535/ https://eprints.nottingham.ac.uk/37535/ |