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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Protein recognition of macrocycles: Binding of anti-HIV metallocyclams to lysozyme
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Protein recognition of macrocycles: Binding of anti-HIV metallocyclams to lysozyme

机译：大环化合物的蛋白质识别：抗HIV金属环素与溶菌酶的结合

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The macrocyclic antiviral drug xylyl-bicyclam blocks entry of HIV into cells by targeting the CXCR4 coreceptor, a seven-helix trans-membrane G-protein-coupled receptor. Its affinity for CXCR4 is enhanced by binding to Cu~(2+), Ni~(2+), or Zn~(2+), Metallocyclams have a rich configurational chemistry and proteins may bind selectively to specific metallocyclam configurations. Our studies of lysozyme reveal structural details of protein-metallocyclam interactions that are important for receptor recognition. Solution NMR studies show that Cu-cyclam interacts with specific tryptophan residues of lysozyme (Trp-62, Trp-63, and Trp-123). Two major binding sites for both Cu-cyclam and Cu_2-xylyl-bicyclam were detected by x-ray crystallography. In the first site, Cu~(2+) in one cyclam ring of Cu_2-xylyl-bicyclam adopts a trans configuration and is coordinated to a carboxylate oxygen of Asp-101, whereas for Cu-cyclam two ring NH groups form H bonds to the carboxylate oxygens of Asp-101, stabilizing an unusual cis (folded) cyclam configuration. For both complexes in this site, a cyclam ring is sandwiched between the indole side chains of two tryptophan residues (Trp-62 and Trp-63). In the second site, a trans cyclam ring is stacked on Trp-123 and H bonded to the backbone carbonyl of Gly-117. We show that there is a pocket in a model of the human CXCR4 coreceptor in which trans and cis configurations of metallobicydam can bind by direct metal coordination to carboxylate side chains, cyclam-NH-carboxylate H bonding, together with hydrophobic interactions with tryptophan residues. These studies provide a structural basis for the design of macrocycles that bind stereospe-cifically to G-coupled and other protein receptors.
机译：大环抗病毒药物二甲苯基-双环酰胺通过靶向CXCR4核心受体（七螺旋跨膜G蛋白偶联受体）来阻止HIV进入细胞。通过与Cu〜（2 +），Ni〜（2+）或Zn〜（2+）结合，增强了其对CXCR4的亲和力。金属环素具有丰富的构型化学，蛋白质可以选择性结合特定的金属环素构型。我们对溶菌酶的研究揭示了蛋白质-金属环素相互作用的结构细节，这对于受体识别非常重要。溶液NMR研究表明，Cu-cyclam与溶菌酶的特定色氨酸残基（Trp-62，Trp-63和Trp-123）相互作用。通过X射线晶体学检测到Cu-Cyclam和Cu_2-二甲苯基-Bicyclam的两个主要结合位点。在第一个位点，一个Cu_2-二甲苯基-Bicyclam环的环中的Cu〜（2+）采用反式构型，并与Asp-101的羧酸氧配位，而对于Cu-cyclam，两个环的NH基团形成H键与Asp-101的羧酸氧，稳定了不寻常的顺式（折叠）环素构型。对于该位点中的两个复合物，一个环蛋白环都夹在两个色氨酸残基（Trp-62和Trp-63）的吲哚侧链之间。在第二个位点，反式环素环堆叠在Trp-123上，H与Gly-117的骨架羰基键合。我们显示，在人类CXCR4受体模型中有一个口袋，其中金属叶突的反式和顺式构型可以通过直接金属配位结合到羧酸盐侧链，环素-NH-羧酸盐H键合以及与色氨酸残基的疏水相互作用而结合。这些研究为大环的设计提供了结构基础，这些大环立体定向地与G偶联的和其他蛋白质受体结合。

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