生物谷：免疫機能是保護我們身體免受病毒、癌,、細菌等侵害的結(jié)構(gòu),，每個人都具備這個結(jié)構(gòu)。異物抗原侵入的話,，身體中就會形成抗體,，集結(jié)免疫細胞來對抗。另外，花粉癥等在發(fā)達國家不斷增加的慢性過敏癥,，被認為是這個免疫機能錯亂造成的,。
擔當這個免疫機能重要作用的一種生物體物質(zhì)是引起哮喘和炎癥的物質(zhì)“白細胞三烯”，它是leukotyieneC4合成酶產(chǎn)生的“leukotyieneC4”和leukotyieneC4被代謝的一些列物質(zhì)群的總稱,。這些物質(zhì)作為比肺的支氣管收縮活性強1000倍的“過敏性反應(yīng)延遲反應(yīng)物質(zhì)”,，比過敏物質(zhì)組胺更受到關(guān)注。
RIKEN同步輻射科學綜合研究中心的宮野構(gòu)造生物物理研究室與美國哈佛大學Brigham婦女醫(yī)院共同合作,，在世界上首次弄清楚了leukotyieneC4合成酶的立體構(gòu)造,，弄清了合成的結(jié)構(gòu),。合成酶是在膜的上方聚集3個,，作成一個正三角形，這個V字形空間是作為酶工作的(觸媒)活性的核心地帶,。而且,，由于leukotyieneC4合成酶是在炎癥免疫中引起強烈病理和生理反應(yīng)的leukotyieneC4合成酶的關(guān)鍵酶，因此,，對于例如花粉癥,、慢性哮喘等還沒有特效藥的慢性過敏疾病來說,，很可能與具有新的作用程序的抗炎癥抗過敏制藥聯(lián)系起來,。
這是RIKEN同步輻射科學綜合研究中心(主任 石川哲也)宮野構(gòu)造生物物理研究室的吾鄉(xiāng)日出夫?qū)Ｂ氀芯繂T、入倉大佑合作研究員,、宮野雅司主任研究員,、美國哈佛大學Brigham婦女醫(yī)院的金岡禧秀副教授、K．Frank Austen教授等共同研究的成果,。
本研究成果刊登于英國的科學雜志Nature網(wǎng)絡(luò)版(7月15日),。（援引日本理化學研究所）
原始出處:
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: [email protected]) or K.F.A. (Email: [email protected]).
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.
