The crystal structure of the active domain of Anopheles anti-platelet protein, a powerful anti-coagulant, in complex with an antibody.
Blood clotting is a vitally important process that must be carefully regulated to prevent blood loss on one hand and thrombosis on the other. Severe injury and hemophilia may be treated with pro-coagulants, whereas risk of obstructive clotting or embolism may be reduced with anti-coagulants. Anti-coagulants are an extremely important class of drug, one of the most widely used types of medication, but there remains a pressing need for novel treatments, however, as present drugs such as warfarin have significant drawbacks. Nature provides a number of examples of anti-coagulant proteins produced by blood-sucking animals, which may provide templates for the development of new small molecules with similar physiological effects. We have, therefore, studied an Anopheles anti-platelet protein from a malaria vector mosquito and report its crystal structure in complex with an antibody. Overall the protein is extremely sensitive to proteolysis, but the crystal structure reveals a stable domain built from two helices and a turn, which corresponds to the functional region. The antibody raised against Anopheles anti-platelet protein prevents it from binding collagen. Our work, therefore, opens new avenues to the development of both novel small molecule anti-clotting agents and anti-malarials.
From the Drug Design Laboratory, Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro, Tsurumi, Yokohama 230-0045, Japan.
Kanako
K
Sugiyama
the Laboratory of Vaccinology and Applied Immunology, Kanazawa University School of Pharmacy, Kakuma-machi, Kanazawa, Japan 920-1192, Japan, and.
Mitsuhiro
M
Iyori
the Laboratory of Vaccinology and Applied Immunology, Kanazawa University School of Pharmacy, Kakuma-machi, Kanazawa, Japan 920-1192, Japan, and.
Asuka
A
Sawaguchi
the Structural Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro, Tsurumi, Yokohama 230-0045, Japan.
Satoko
S
Akashi
From the Drug Design Laboratory, Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro, Tsurumi, Yokohama 230-0045, Japan.
Jeremy R H
JR
Tame
From the Drug Design Laboratory, Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro, Tsurumi, Yokohama 230-0045, Japan, park@tsurumi.yokohama-cu.ac.jp.
Sam-Yong
SY
Park
the Laboratory of Vaccinology and Applied Immunology, Kanazawa University School of Pharmacy, Kakuma-machi, Kanazawa, Japan 920-1192, Japan, and shigeto@p.kanazawa-u.ac.jp.
Shigeto
S
Yoshida
D000595:Amino Acid Sequence; D000818:Animals; D000852:Anopheles / Q000378:metabolism*; D000906:Antibodies / Q000276:immunology*; D000925:Anticoagulants / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D001483:Base Sequence; D001777:Blood Coagulation; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D017931:DNA Primers; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D016133:Polymerase Chain Reaction; D011487:Protein Conformation; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000906:Antibodies; D000925:Anticoagulants; D017931:DNA Primers
Anti-coagulant; Antibody Engineering; Blood Coagulation Factors; Collagen; Crystal Structure; Malaria