生物谷：免疫机能是保护我们身体免受病毒、癌、细菌等侵害的结构，每个人都具备这个结构。异物抗原侵入的话，身体中就会形成抗体，集结免疫细胞来对抗。另外，花粉症等在发达国家不断增加的慢性过敏症，被认为是这个免疫机能错乱造成的。
担当这个免疫机能重要作用的一种生物体物质是引起哮喘和炎症的物质“白细胞三烯”，它是leukotyieneC4合成酶产生的“leukotyieneC4”和leukotyieneC4被代谢的一些列物质群的总称。这些物质作为比肺的支气管收缩活性强1000倍的“过敏性反应延迟反应物质”，比过敏物质组胺更受到关注。
RIKEN同步辐射科学综合研究中心的宫野构造生物物理研究室与美国哈佛大学Brigham妇女医院共同合作，在世界上首次弄清楚了leukotyieneC4合成酶的立体构造，弄清了合成的结构。合成酶是在膜的上方聚集3个，作成一个正三角形，这个V字形空间是作为酶工作的(触媒)活性的核心地带。而且，由于leukotyieneC4合成酶是在炎症免疫中引起强烈病理和生理反应的leukotyieneC4合成酶的关键酶，因此，对于例如花粉症、慢性哮喘等还没有特效药的慢性过敏疾病来说，很可能与具有新的作用程序的抗炎症抗过敏制药联系起来。
这是RIKEN同步辐射科学综合研究中心(主任 石川哲也)宫野构造生物物理研究室的吾乡日出夫专职研究员、入仓大佑合作研究员、宫野雅司主任研究员、美国哈佛大学Brigham妇女医院的金冈禧秀副教授、K．Frank Austen教授等共同研究的成果。
本研究成果刊登于英国的科学杂志Nature网络版(7月15日)。（援引日本理化学研究所）
原始出处:
Nature advance online publication 15 July 2007 | doi:10.1038/nature05936; Received 29 January 2007; Accepted 17 May 2007; Published online 15 July 2007
Crystal structure of a human membrane protein involved in cysteinyl leukotriene biosynthesis
Hideo Ago1,3, Yoshihide Kanaoka2,3, Daisuke Irikura1,2,3, Bing K. Lam2, Tatsuro Shimamura1, K. Frank Austen2 & Masashi Miyano1
Structural Biophysics Laboratory, RIKEN SPring-8 Center, Harima Institute, 1-1-1 Kouto, Sayo, Hyogo 679-5148, Japan
Department of Medicine, Harvard Medical School and Division of Rheumatology, Immunology, and Allergy, Brigham Women's Hospital, Boston, Massachusetts 02115, USA
These authors contributed equally to this work.
Correspondence to: K. Frank Austen2Masashi Miyano1 Correspondence and requests for materials should be addressed to M.M. (Email: miyano@spring8.or.jp) or K.F.A. (Email: fausten@rics.bwh.harvard.edu).
The cysteinyl leukotrienes, namely leukotriene (LT)C4 and its metabolites LTD4 and LTE4, the components of slow-reacting substance of anaphylaxis1, 2, are lipid mediators of smooth muscle constriction3, 4, 5 and inflammation6, 7, particularly implicated in bronchial asthma8, 9. LTC4 synthase (LTC4S), the pivotal enzyme for the biosynthesis of LTC4 (ref. 10), is an 18-kDa integral nuclear membrane protein11, 12 that belongs to a superfamily of membrane-associated proteins in eicosanoid and glutathione metabolism that includes 5-lipoxygenase-activating protein, microsomal glutathione S-transferases (MGSTs), and microsomal prostaglandin E synthase 1 (ref. 13). LTC4S conjugates glutathione to LTA4, the endogenous substrate derived from arachidonic acid through the 5-lipoxygenase pathway14. In contrast with MGST2 and MGST3 (refs 15, 16), LTC4S does not conjugate glutathione to xenobiotics17. Here we show the atomic structure of human LTC4S in a complex with glutathione at 3.3 Å resolution by X-ray crystallography and provide insights into the high substrate specificity for glutathione and LTA4 that distinguishes LTC4S from other MGSTs. The LTC4S monomer has four transmembrane -helices and forms a threefold symmetric trimer as a unit with functional domains across each interface. Glutathione resides in a U-shaped conformation within an interface between adjacent monomers, and this binding is stabilized by a loop structure at the top of the interface. LTA4 would fit into the interface so that Arg 104 of one monomer activates glutathione to provide the thiolate anion that attacks C6 of LTA4 to form a thioether bond, and Arg 31 in the neighbouring monomer donates a proton to form a hydroxyl group at C5, resulting in 5(S)-hydroxy-6(R)-S-glutathionyl-7,9-trans-11,14-cis-eicosatetraenoic acid (LTC4). These findings provide a structural basis for the development of LTC4S inhibitors for a proinflammatory pathway mediated by three cysteinyl leukotriene ligands whose stability and potency are different and by multiple cysteinyl leukotriene receptors whose functions may be non-redundant.
