Structure and dynamics of apical membrane antigen 1 from Plasmodium falciparum FVO

San Sui Lim, Wei W Yang, Bankala Krishnarjuna, Komagal Kannan Sivaraman, Indu Rajmohan Chandrashekaran, Itamar Kass, Christopher Andrew MacRaild, Shane Devine, Cael Debono, Robin F Anders, Martin Scanlon, Peter John Scammells, Raymond Stanley Norton, Sheena McGowan

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Apical membrane antigen 1 (AMA1) interacts with RON2 to form a protein complex that plays a key role in the invasion of host cells by malaria parasites. Blocking this protein-protein interaction represents a potential route to controlling malaria and related parasitic diseases, but the polymorphic nature of AMA1 has proven to be a major challenge to vaccine-induced antibodies and peptide inhibitors exerting strain-transcending inhibitory effects. Here we present the X-ray crystal structure of AMA1 domains I and II from Plasmodium falciparum strain FVO. We compare our new structure to those of AMA1 from P. falciparum 3D7 and Plasmodium vivax. A combination of normalized B factor analysis and computational methods has been used to investigate the flexibility of the domain I loops and how this correlates with their roles in determining the strain specificity of human antibody responses and inhibitory peptides. We also investigated the domain II loop, a key region involved in inhibitor binding, by comparison of multiple AMA1 crystal structures. Collectively, these results provide valuable insights that should contribute to the design of strain-transcending agents targeting P. falciparum AMA1.
Original languageEnglish
Pages (from-to)7310 - 7320
Number of pages11
JournalBiochemistry
Volume53
Issue number46
DOIs
Publication statusPublished - 2014

Cite this

@article{2bf48d2692c645249c4360b9c685e840,
title = "Structure and dynamics of apical membrane antigen 1 from Plasmodium falciparum FVO",
abstract = "Apical membrane antigen 1 (AMA1) interacts with RON2 to form a protein complex that plays a key role in the invasion of host cells by malaria parasites. Blocking this protein-protein interaction represents a potential route to controlling malaria and related parasitic diseases, but the polymorphic nature of AMA1 has proven to be a major challenge to vaccine-induced antibodies and peptide inhibitors exerting strain-transcending inhibitory effects. Here we present the X-ray crystal structure of AMA1 domains I and II from Plasmodium falciparum strain FVO. We compare our new structure to those of AMA1 from P. falciparum 3D7 and Plasmodium vivax. A combination of normalized B factor analysis and computational methods has been used to investigate the flexibility of the domain I loops and how this correlates with their roles in determining the strain specificity of human antibody responses and inhibitory peptides. We also investigated the domain II loop, a key region involved in inhibitor binding, by comparison of multiple AMA1 crystal structures. Collectively, these results provide valuable insights that should contribute to the design of strain-transcending agents targeting P. falciparum AMA1.",
author = "Lim, {San Sui} and Yang, {Wei W} and Bankala Krishnarjuna and {Kannan Sivaraman}, Komagal and Chandrashekaran, {Indu Rajmohan} and Itamar Kass and MacRaild, {Christopher Andrew} and Shane Devine and Cael Debono and Anders, {Robin F} and Martin Scanlon and Scammells, {Peter John} and Norton, {Raymond Stanley} and Sheena McGowan",
year = "2014",
doi = "10.1021/bi5012089",
language = "English",
volume = "53",
pages = "7310 -- 7320",
journal = "Biochemistry",
issn = "0006-2960",
number = "46",

}

Structure and dynamics of apical membrane antigen 1 from Plasmodium falciparum FVO. / Lim, San Sui; Yang, Wei W; Krishnarjuna, Bankala; Kannan Sivaraman, Komagal; Chandrashekaran, Indu Rajmohan; Kass, Itamar; MacRaild, Christopher Andrew; Devine, Shane; Debono, Cael; Anders, Robin F; Scanlon, Martin; Scammells, Peter John; Norton, Raymond Stanley; McGowan, Sheena.

In: Biochemistry, Vol. 53, No. 46, 2014, p. 7310 - 7320.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Structure and dynamics of apical membrane antigen 1 from Plasmodium falciparum FVO

AU - Lim, San Sui

AU - Yang, Wei W

AU - Krishnarjuna, Bankala

AU - Kannan Sivaraman, Komagal

AU - Chandrashekaran, Indu Rajmohan

AU - Kass, Itamar

AU - MacRaild, Christopher Andrew

AU - Devine, Shane

AU - Debono, Cael

AU - Anders, Robin F

AU - Scanlon, Martin

AU - Scammells, Peter John

AU - Norton, Raymond Stanley

AU - McGowan, Sheena

PY - 2014

Y1 - 2014

N2 - Apical membrane antigen 1 (AMA1) interacts with RON2 to form a protein complex that plays a key role in the invasion of host cells by malaria parasites. Blocking this protein-protein interaction represents a potential route to controlling malaria and related parasitic diseases, but the polymorphic nature of AMA1 has proven to be a major challenge to vaccine-induced antibodies and peptide inhibitors exerting strain-transcending inhibitory effects. Here we present the X-ray crystal structure of AMA1 domains I and II from Plasmodium falciparum strain FVO. We compare our new structure to those of AMA1 from P. falciparum 3D7 and Plasmodium vivax. A combination of normalized B factor analysis and computational methods has been used to investigate the flexibility of the domain I loops and how this correlates with their roles in determining the strain specificity of human antibody responses and inhibitory peptides. We also investigated the domain II loop, a key region involved in inhibitor binding, by comparison of multiple AMA1 crystal structures. Collectively, these results provide valuable insights that should contribute to the design of strain-transcending agents targeting P. falciparum AMA1.

AB - Apical membrane antigen 1 (AMA1) interacts with RON2 to form a protein complex that plays a key role in the invasion of host cells by malaria parasites. Blocking this protein-protein interaction represents a potential route to controlling malaria and related parasitic diseases, but the polymorphic nature of AMA1 has proven to be a major challenge to vaccine-induced antibodies and peptide inhibitors exerting strain-transcending inhibitory effects. Here we present the X-ray crystal structure of AMA1 domains I and II from Plasmodium falciparum strain FVO. We compare our new structure to those of AMA1 from P. falciparum 3D7 and Plasmodium vivax. A combination of normalized B factor analysis and computational methods has been used to investigate the flexibility of the domain I loops and how this correlates with their roles in determining the strain specificity of human antibody responses and inhibitory peptides. We also investigated the domain II loop, a key region involved in inhibitor binding, by comparison of multiple AMA1 crystal structures. Collectively, these results provide valuable insights that should contribute to the design of strain-transcending agents targeting P. falciparum AMA1.

UR - http://pubs.acs.org/doi/pdf/10.1021/bi5012089

U2 - 10.1021/bi5012089

DO - 10.1021/bi5012089

M3 - Article

VL - 53

SP - 7310

EP - 7320

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 46

ER -