title: Human β-defensin 4 - defensin without the "twist".
abstract: β-defensins are small, cysteine-rich, cationic peptides that contribute to various processes related to both arms of host defense, the innate and adaptive immunities. All β-defensins are potent antimicrobials with activity targeting a broad range of pathogens. Some human β-defensins (hBDs) are also capable of binding and activating specific chemokine receptors, leading to chemotaxis of receptor-presenting cells. Two receptors identified as targets of specific human β-defensins are CCR2 and CCR6, both members of the seven-transmembrane family of chemokine receptors. Currently, around 50 open reading frames (ORFs) identified in the human genome encode proteins that have signatures characteristic of β-defensins. Of those, only three, hBD1-3, have been thoroughly characterized to date, including a detailed structural description of their molecules. In addition, limited information on biological and bactericidal properties is available for hBD4, as well as the solution structure of hBD6. The crystal structure of hBD4, determined here at resolution of 1.60 Å, indicates significant structural differences between this molecule and those reported previously for other hBDs. Crystallographic studies indicate a possibility of unique dimerization of hBD4, confirmed by solution studies using analytical ultracentrifugation. In contrast to hBD1-3, hBD4 does not induce CCR6-mediated chemotaxis. This observation can be attributed to an unusual conformation of the hBD4 N-terminus. In agreement with previously published reports, hBD4 was shown to be a potent antibacterial agent, as demonstrated by results of assays with E. coli ATCC 25922 cells.
authors.affiliation: Wydział Chemii, Katedra Chemii Organicznej, Uniwersytet Gdański, ul. Wita Stwosza 63, 80-308 Gdańsk, Polska.
authors.forename: Adam
authors.initials: A
authors.lastname: Prahl
authors.affiliation: Division of Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Marzena
authors.initials: M
authors.lastname: Pazgier
authors.affiliation: Macromolecular Crystallography Laboratory, Center for Cancer Research, National Cancer Institute, Frederick MD 21702, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Alexandratos
authors.affiliation: Macromolecular Crystallography Laboratory, Center for Cancer Research, National Cancer Institute, Frederick MD 21702, USA.
authors.forename: Jacek
authors.initials: J
authors.lastname: Lubkowski
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D011487:Protein Conformation; D023083:beta-Defensins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; C106641:DEFB4A protein, human; D023083:beta-Defensins
keywords: Human defensins; X-ray; antimicrobial; chemotaxis; crystallography; oligomerization; structure