亲免疫蛋白p23(也称为PTGES3)选择性地与HSP90的atp结合状态结合。p23稳定了HSP90的封闭状态，从而削弱了STIP1(HOP)的结合并促进其退出复合物(McLaughlin H et al. 2006;Karagöz GE et al. 2011)。当p23在没有亲免疫蛋白的情况下或与FKBP51 (FKBP5)一起加入客户端转移复合体时，p23的两个拷贝被合并，同时HSP70和HOP丢失(Ebong等，2016)。相比之下，在FKBP52 (FKBP4)存在时，没有观察到与两个p23亚基的稳定复合物;HSP70、HOP和p23的排出发生在仅包含一个p23亚基的复合体的低种群中(Ebong等，2016)。

类固醇激素受体(SHRs)是一种穿梭蛋白，它不断地进行核输入和输出。尽管各种SHRs在细胞中有不同的静息定位，但配体添加后的快速且几乎完全的核易位是几乎所有SHRs(已经核雌激素受体除外)的共同行为。Reactome事件表明，通过向SHR:HSP90复合体募集大亲免疫蛋白FKBP52 (FKBP4)，微管相关核易位(Galigniana et al. 2002;Wochnik et al. 2005;Davies and Sanchez 2005;Galigniana MD et al. 2010)。FKBP52将糖皮质激素受体(GR):HSP90和矿皮质激素受体(MR):HSP90复合物连接到动力蛋白/动力蛋白马达，促进细胞质SHR向细胞核的运输(Wochnik et al. 2005;Gallo L et al. 2007)。此外，在共表达动力蛋白的成纤维细胞中，GR的细胞质-核运动被阻断，后者将动力蛋白与其产物分离(Harrell et al. 2004)。FKBP52通过肽基脯氨酸异构酶(PPIase)结构域直接与运动蛋白动力蛋白结合(Wochnik et al. 2005)。 Interestingly, the PPIase domain of another immunophilin FKBP51 (FKBP5) is unable to interact with dynein. Without hormone, FKBP51 is the major immunophilin in GR:HSP90 complexes, whereas after hormone treatment, FKBP52 rapidly replaces FKBP51 such that these complexes are now able to translocate to the nucleus with an accelerated rate (Davies et al. 2002). In addition, replacement of FKPB52 by FKBP51 favored the cytoplasmic localization of MR (Galigniana MD et al. 2010). On the other hand, GR was apparently able to translocate to the nucleus with the same rate even if the microtubule network was completely disrupted suggesting that he subcellular localization of SHRs can be controlled by several coexisting mechanisms (Czar et al. 1995). Indeed, in yeast and mammalian cells liganded and unliganded SHRs can bind several importins to be translocated into the nucleus (Freedman and Yamamoto 2004; Picard and Yamamoto 1987). In addition, importin beta and the integral nuclear pore glycoprotein NUP62 interact with HSP90, HSP70, p23, and the TPR domain proteins FKBP52 and PP5. NUP62 and GR are able to interact in a more efficient manner when chaperoned by the HSP90-based heterocomplex (Echeverria et al. 2009). GR cross-linked to the HSP90 heterocomplex is able to translocate to the nucleus in digitonin-permeabilized cells treated with steroid, suggesting that GR could pass through the pore in its untransformed state (Echeverria et al. 2009).

HSP90的伴随功能与其atp酶活性相耦合。我们目前对Hsp90的atp酶机制的理解主要基于对酿酒酵母Hsp90复合物的结构和功能的研究(Meyer P et al. 2003, 2004;Ali MM et al. 2006;Prodromou C等人，2000;Prodromou C 2012)。人类HSP90的三磷酸腺苷酶循环尚不清楚，但几项研究表明，潜在的酶机制和伴随三磷酸腺苷酶循环的一系列构象变化在这两个物种中是高度相似的(Richter K等人，2008;Vaughan CK et al. 2009)。一旦ATP结合，它有助于稳定封闭的ATP盖状态，其中ATP的γ -磷酸提供氢键，促进ATP盖与n端结构域(NTD)的稳定结合(Ali MM等人，2006;Prodromou C等人，2000;Chadli A et al. 2000)。 The association of ATP with NTD then stimulates structural changes in NTD and in the middle domain that are likely to involve movements of the ATP lid segment within each N-terminal domain that locates over the bound ATP. The movement of the lids exposes surface residues that are subsequently involved in transient dimerization of the N-terminal domains of HSP90 (Ali MM et al. 2006; Prodromou C et al. 2000; Chadli A et al. 2000). Furthermore, the intrachain associations of NTD with the middle domain leads to the active conformation of the catalytic loop of HSP90, which commits the ATP for hydrolysis (Meyer P et al. 2003). The subsequent conformational changes upon ATP binding are regulated by co-chaperone activities. For example, arrangement of the STIP1 domains in the complex seems to prevent the NTDs dimerization of HSP90 monomers and total closure of the HSP90 dimer that is required for an efficient HSP90-mediated ATP hydrolysis (Southworth DR and Agard DA 2011; Alvira S et al. 2014). In addition, client protein binding to HSP90 was found to increase ATPase activity of HSP90 up to 200-fold (McLaughlin SH et al. 2002).After hydrolysis of ATP the ligand-bound steroid hormone receptor (SHR) is released from HSP90 complex. The Reactome module describes ATPase activity of HSP90 in the nucleus, however it is not entirely clear whether cytosolic hormone-bound SHR translocates through the nuclear pores before or after ATP-dependent dissociation from the HSP90 complex.

质谱分析表明，FKBP51 (FKBP5)和FKBP52 (FKBP4)与GR:HSP90:STIP1:HSP70:ATP形成类似的配合物(Ebong IO et al. 2016)。在没有激素的情况下，FKBP51是GR:HSP90复合物中的主要亲免疫蛋白，而在激素治疗后，FKBP52迅速取代FKBP51 (Davies et al.， 2002)。

FKBP52(也称为大亲免疫蛋白FKBP4)是一种含有四肽重复(TPR)结构域的共伴侣，它结合HSP90的c端序列基序(MEEVD) (Wu B et al. 2004;Davies and Sanchez, 2005)。受体异质复合物中FKBP的化学计量是根据交联复合物的大小来确定的，在人PR、ER和小鼠GR中获得了一个受体分子和两个HSP90分子与一个FKBP52分子的比例(Rexin M et al. 1992;Rehberger P et al. 1992;Segnitz B and Gehring U 1995)。质谱分析表明，FKBP51 (FKBP5)和FKBP52 (FKBP4)与GR:HSP90:STIP1:HSP70:ATP形成类似的配合物(Ebong IO et al. 2016)。FKBP52 (FKBP4)与其他亲免疫蛋白的结合可能削弱含有TPR结构域的STIP1蛋白与HSP90复合物的结合(Li et al. 2011)。FKBP52 (FKBP4)是能够结合免疫抑制药物的细胞内蛋白免疫亲蛋白(IMM)蛋白家族的成员，免疫亲蛋白一词由此而来(Pratt and Toft 1997;Kang et al. 2008)。这些蛋白质也被称为肽基-脯氨酸顺式/反式异构酶(PPIases)，因为它们具有将脯氨酸键从顺式转化为反式的能力，这是蛋白质折叠中的一个限速步骤(Harding等人，1989; Standaert et al. 1990; Galat 2003; Davies and Sanchez 2005). In addition to the PPIase and TPR domains, there are two additional domains - the nucleotide-binding domain (also called FKBD2 in FKBP proteins) where ATP binds and the calmodulin-binding domain, a poorly characterized domain able to interact with calmodulin.

FK506结合蛋白5 (FKBP51，也称为FKBP5)是细胞内蛋白中亲免疫蛋白(IMM)蛋白家族的成员。IMM家族的特征结构域是肽基脯氨酸顺式/反式异构酶(PPIase)结构域，它又是药物结合结构域。imm根据其结合免疫抑制药物的能力进行分类——CyPs(亲环蛋白)结合环孢素A (CsA)， FKBPs (FK506结合蛋白)结合FK506 (Pratt and Toft 1997;Kang et al. 2008)。除了PPIase结构域，还有三个额外的结构域——ATP结合的核苷酸结合结构域(在FKBP蛋白中也称为FKBD2)，钙调素结合结构域，一个特征不明确的结构域，能够与钙调素相互作用，以及四肽重复(TPR)结构域，34个氨基酸序列串联重复，FKBPs通过该序列与HSP90 c端序列MEEVD结合(Davies等，2005;Wu et al. 2004)。质谱分析表明，FKBP51 (FKBP5)和FKBP52 (FKBP4)与GR:HSP90:STIP1:HSP70:ATP形成类似的配合物(Ebong IO et al. 2016)。FKBP51 (FKBP5)与其他亲免疫蛋白结合可能会削弱含有TPR结构域的STIP1蛋白与HSP90复合物的关联(Li et al. 2011)。

亲免疫蛋白p23(也称为PTGES3)选择性地与HSP90的atp结合状态结合。p23稳定了HSP90的封闭状态，从而削弱了STIP1(HOP)的结合并促进其退出复合物(McLaughlin H et al. 2006;Karagöz GE et al. 2011)。当FKBP51 (FKBP5)存在时，通过排除HSP70和STIP1(HOP)形成稳定的中间FKBP51:GR:HSP90:p23 (Ebong I et al. 2016)。

类固醇激素受体(SHRs)是细胞内的转录因子，可以通过将特异性配体(类固醇激素(SH))结合到配体结合结构域(LBD)而激活(Ray DW等，1999;派克等人，1999;Bledsoe RK et al. 2002;李毅等，2005;Kumar R和McEwan IJ 2012;Kumar R et al. 2011;Williams SP和Sigler PB 1998;Tanenbaum DM et al. 1998;Lusher SJ et al. 2012)。LBD (e区)位于受体的c端一半，除了配体结合功能外，还包含转录激活功能(AF2)，二聚化，热休克蛋白结合，分子间沉默和分子内抑制的序列(Kumar R和McEwan IJ 2012)。 The binding of hormone acts as an allosteric switch to regulate SHR-DNA and SHR-protein interactions, including interdomain interactions and/or dimerization (Kumar R and McEwan IJ 2012).SHs are synthesized from cholesterol in the adrenal cortex (glucocorticoids, mineralocorticoids, and adrenal androgens), the testes (testicular androgens, estrogen), and the ovary and placenta (estrogen and progestogen or progestins) (Payne AH and Hales DB 2004; Hu J et al. 2010;). SHs reach their target cells via the blood, where they are bound to specific carrier proteins (Grishkovskaya I et al. 2000; Hammond GL 2016). SHs detach from the carrier proteins and because of their lipophilic nature readily diffuse through the plasma membrane of cells (Oren I et al. 2004). Within the target cells SHs bind to steroid hormone receptors (SHRs) which are present in a heterocomplex with heat shock protein HSP90 and co-chaperones (e.g., immunophilins p23) (Echeverria PC and Picard D 2010). The ATP-bound form of HSP90 and chaperone-mediated conformational changes are required to keep SHRs in a ligand binding-competent state (McLaughlin SH et al. 2002; Pratt WB et al. 2008; Krukenberg KA et al. 2011). Here, the androgens testosterone (TEST), dihydrotestosterone (DHTEST), androst-4-en-3,17-dione (ANDST) and 6-dehydrotestosterone bind the androgen receptor (AR), within the HSP90 chaperone complex.

类固醇激素受体(SHRs)是细胞内的转录因子，可以通过将特异性配体(即类固醇激素(SH))结合到配体结合结构域(LBD)而激活(Ray DW等，1999;派克等人，1999;Bledsoe RK et al. 2002;李毅等，2005;Kumar R和McEwan IJ 2012;Kumar R et al. 2011;Williams SP和Sigler PB 1998;Tanenbaum DM et al. 1998;Lusher SJ et al. 2012)。LBD (e区)位于受体的c端一半，除了配体结合功能外，还包含转录激活功能(AF2)，二聚化，热休克蛋白结合，分子间沉默和分子内抑制的序列(Kumar R和McEwan IJ 2012)。 The binding of hormone acts as an allosteric switch to regulate SHR-DNA and SHR-protein interactions, including interdomain interactions and/or dimerization (Kumar R and McEwan IJ 2012).SHs are synthesized from cholesterol in the adrenal cortex (glucocorticoids, mineralocorticoids, and adrenal androgens), the testes (testicular androgens, estrogen), and the ovary and placenta (estrogen and progestogen or progestins) (Payne AH and Hales DB 2004; Hu J et al. 2010;). SHs reach their target cells via the blood, where they are bound to specific carrier proteins (Grishkovskaya I et al. 2000; Hammond GL 2016). SHs detach from the carrier proteins and because of their lipophilic nature readily diffuse through the plasma membrane of cells (Oren I et al. 2004). Within the target cells SHs bind to steroid hormone receptors (SHRs) which are present in a heterocomplex with heat shock protein HSP90 and co-chaperones (e.g., immunophilins p23) (Echeverria PC and Picard D 2010). The ATP-bound form of HSP90 and chaperone-mediated conformational changes are required to keep SHRs in a ligand binding-competent state (McLaughlin SH et al. 2002; Pratt WB et al. 2008; Krukenberg KA et al. 2011).

人类HSP70家族包括至少8个独特的基因产物，它们在氨基酸序列、表达水平和亚细胞定位方面各不相同(Daugaard M et al. 2007)。HSP70家族成员显示出高度保守的氨基酸序列和结构域结构，包括:结合和水解ATP的ATP酶n端结构域(NBD)，与暴露的客户多肽疏水片段结合并以动态依赖ATP的方式促进其溶解度和/或折叠的底物结构域(SBD)，以及为底物结构域提供“盖子”的c结构域(Zhang P et al. 2014;brochieri L et al. 2008;Wisniewska M et al. 2010)。保守结构域结构巩固了Hsp70蛋白的伴侣功能，使它们能够结合和释放疏水氨基酸的延伸，这些氨基酸以atp依赖的方式被错误折叠的球状蛋白暴露(Takayama S等人，1999;Mayer MP 2013;Daugaard M et al. 2007)。热休克蛋白40 (HSP40)与未折叠的客户蛋白的初始结合阻止其聚集并将其“传递”给HSP70。HSP70的底物结合能力取决于其与ATP或ADP的结合状态(Kityk R et al. 2012;齐荣等，2013)。 Client substrates enter the HSP70 functional cycle by binding the ATP form of the chaperone, which has lower substrate affinity but faster binding and release rates compared with the ADP state. Interaction of the client in the cleft results in conformational changes in NBD that modestly increase ATP hydrolysis. Second, a transient interaction of HSP70 with J-protein co-chaperone HSP40, which has a higher affinity to ATP-bound HSP70 than ADP-bound HSP70, also stimulates the ATPase activity of HSP70 (Wittung-Stafshede P et al. 2003).

热休克蛋白70 (HSP70)蛋白结合并释放客户多肽，在cochaper酮介导的构象变化循环中，与ATP结合和水解相结合(Mayer MP 2013)。所有HSP70伴侣蛋白的整体结构域都是进化保守的:具有atp酶活性的n端核苷酸结合域(NBD)通过一个柔性连接体连接到c端多肽底物结合域(SBD)。我们对HSP70结构和功能的机制理解大多来自于对大肠杆菌HSP70家族成员DnaK的分析(Pellecchia M et al. 2000;Schuermann, JP et al. 2008;Bertelsen EB et al. 2009;Kityk R et al. 2012;齐荣等，2013)。细菌DnaK的伴侣作用涉及其两个功能域NBD和SBD之间的变构控制机制。ATP结合和水解调节细菌HSP70蛋白对多肽的亲和力，多肽结合刺激ATP水解(Mayer MP等，2000;Kityk R et al. 2012; Qi R et al. 2013). Also in the ATP-bound form, the lid domain remains open, which facilitates transient interactions with substrates. Following ATP hydrolysis, a conformational change releases the SBD, resulting in closure of the lid and a ~10-fold increase in the affinity for substrate (Wittung-Stafshede P et al. 2003; Slepenkov SV and Witt SN 2002). The conformation change associated with ATP hydrolysis is communicated through a key proline switch and involves the conserved, hydrophobic linker that connects the NBD to the SBD (Vogel M et al. 2006; Swain JF et al. 2007). ATP hydrolysis is essential for HSP70 chaperones, but the intrinsic ATPase rate is very low (Chang L et al. 2008). This ATPase activity of HSP70 is stimulated by protein substrates in synergism with J domain cochaperones (HSP40s) (Karzai AW and McMacken R 1996; Russell R et al. 1999; Laufen T et al. 1999; Landry SJ 2003; Wittung-Stafshede P et al. 2003).The HSP70 family of chaperone proteins is one of the most conserved protein families in evolution (Takayama S et al. 1999; Boorstein WR et al. 1994; Brocchieri L et al. 2008). The sequence alignment of eukaryotic and bacterial HSP70 proteins revealed that the human HSP70 SBD is highly homologous to the DnaK SBD (51% sequence identity in the full-length protein and 47% identity in the SBD) (Zhang P et al. 2014). Moreover, the crystal structure of the substrate-bound human HSP70-SBD resembled the overall fold of the corresponding domain in the substrate-bound DnaK structures, confirming a similar overall architecture of the orthologous bacterial and human HSP70 proteins (Zhang P et al. 2014). Structures of nucleotide-binding domains of four human HSP70 isoforms: HSPA1L, HSPA2, HSPA6 and HSPA5 also support the view that the NBDs of human HSP70 function by conserved mechanisms (Wisniewska M et al. 2014). Structural analysis of a functionally intact bovine Hsp70 family member Hsc70 together with analysis of mutants in the interdomain linker and interface support the allosteric mechanism of the mammalian HSP70 chaperones (Wilbanks SM and McKay DB 1998; Jiang J et al. 2005).

应激诱导磷酸化蛋白1 (STIP1，也被称为hsp70 -HSP90组织蛋白或HOP)作为细胞组装机器的一部分，在热休克蛋白(hsp70)和HSP90之间的相互作用中起中介作用。它还能调节HSP70和HSP90的atp酶活性，从而促进客户蛋白在两者之间的转移。STIP1是一个单体蛋白，由三个参与蛋白相互作用的四肽重复结构域(TPR1, TPR2A, TPR2B)和两个参与客户端激活的小天冬氨酸-脯氨酸重复结构域(DP1, DP2)组成(Scheufler C et al. 2000;Nelson GM et al. 2003;Yi F et al. 2010;Schmid AB et al. 2012)。STIP1的柔性连接器(HOP)连接TPR1-DP1和TPR2A-TPR2B-DP2模块，排列为TPR1-DP1-TPR2A-TPR2B-DP2 (Scheufler C et al. 2000)。生化和晶体学分析表明，STIP1的TPR结构域与HSP70或HSP90伴侣的c端MEEVD基序特异性相互作用;TPR2A优先结合HSP90，而TPR1和TPR2B结合HSP70 (Scheufler C et al. 2000;Carrigan PE et al. 2006; Schmid AB et al. 2012). Furthermore, cryoelectron microscopy (cryo-EM) reconstruction of the human HSP90:STIP1 complex revealed that STIP1 may also form interactions in several other parts of HSP90, pre-organizing N-terminal domains (NTDs) of HSP90 and thus increasing accessibility of the nucleotide-binding pocket (Southworth DR and Agard DA 2011). STIP1 stabilizes an alternate HSP90 open state where hydrophobic client-binding surfaces of HSP90 monomers have converged remaining accessible for client loading (Southworth DR and Agard DA 2011). STIP1 is positioned with a TPR1 domain extending from the HSP90 dimer cleft remaining available for an interaction with HSP70. In the STIP1-stabilized HSP90 conformation the N-terminal domains have rotated to match the closed ATP conformation. However, the arrangement of the STIP1 domains in the complex seems to prevent the NTDs dimerization of HSP90 monomers and total closure of the HSP90 dimer that is required for an efficient HSP90-mediated ATP hydrolysis (Southworth DR and Agard DA 2011; Alvira S et al. 2014). HSP70, in the ADP state, readily binds HSP90:STIP1, forming a client-loading complex HSP90:STIP1:HSP70:client protein (Hernández MP et al. 2002). Structural studies of GR-LBD (the ligand-binding domain of the glucocorticoid receptor) bound to HSP90:STIP1:HSP70 complex showed that one STIP1 molecule binds to the HSP90 dimer and through domain rearrangement, gives rise to two main conformations, an extended structure that recognizes and interacts with HSP70, and a compact one in which HSP70 is in contact with one HSP90 monomer (Alvira S et al. 2014). Movement between these two modes is thought to deliver the HSP70-bound substrate to the side of the HSP90 dimer opposite the site of STIP1 binding (Alvira S et al. 2014). Following client delivery by HSP70 and STIP1 release, HSP90:ATP converts to the closed ATP hydrolysis-active state to complete the chaperone cycling.

分子伴侣热休克蛋白90 (HSP90)是一种同源二聚体。每个HSP90原聚体包含三个灵活连接的区域，n端atp结合域(NTD)，中间域和C端二聚化域(Prodromou C et al. 1997;Pearl LH和propropromou C 2006)。HSP90二聚体是一种动态分子，ATP的结合和水解与构象变化有关(Obermann WM et al. 1998;Krukenberg KA et al. 2011;Li J和Buchner J 2013;Prodromou C 2012)。分离的酵母和人类HSP90的n端结构域(NTD)与ATP、ADP和腺苷酸二磷酸(AMP-PNP，一种不可水解的ATP类似物)结合的结构表明，在HSP90开放载子状态下，核苷酸结合在NTD的间隙深处(Prodromou C et al.1997;Meyer P et al. 2003, 2004;Colombo G et al. 2008; Li J et al. 2012). The structural studies of NTD of human HSP90 with antitumor agent geldanamycin (that acts as an ADP/ATP mimetic) support the polar interactions in the binding pocket described for yeast Hsp90 and ADP or ATP (Stebbins CE et al. 1997; Prodromou C et al.1997; Grenert JP et al. 1997). Once ATP is bound it helps to stabilize the closed ATP lid state, in which the gamma-phosphate of ATP provides a hydrogen bonding that promotes a stable association of the ATP lid with NTD. The association of ATP or AMP-PNP with NTD then stimulates structural changes in NTD. NMR analysis of human full-length HSP90 protein with and without ATP confirmed that ATP binding led to conformational changes in NTD (Karagöz GE et al. 2010). No structural changes were observed in the middle and C-terminal domains (Karagöz GE et al. 2010). However, other studies suggest that ATP-dependent conformational changes occur both in NTD and in the middle domain of HSP90 (Ali MM et al. 2006; Prodromou C et al. 2000; Chadli A et al. 2000; Meyer P et al. 2003). The changes are likely to involve movements of the ATP lid segment within each N-terminal domain that locates over the bound ATP (Ali MM et al. 2006; Prodromou C et al. 2000; Chadli A et al. 2000). The movement of the lids exposes surface residues that are subsequently involved in transient dimerization of the N-terminal domains of HSP90 (Ali MM et al. 2006; Prodromou C et al. 2000; Chadli A et al. 2000). The subsequent conformational changes upon ATP binding are regulated by co-chaperone activities. For example, arrangement of the STIP1 domains in the complex seems to prevent the NTDs dimerization of HSP90 monomers and total closure of the HSP90 dimer that is required for an efficient HSP90-mediated ATP hydrolysis (Southworth DR and Agard DA 2011; Alvira S et al. 2014). Thus, ATP binding coupled to co-chaperone-mediated loading of client protein to HSP90 complex regulates ATPase activity of HSP90.

类固醇激素受体(SHRs)是细胞内的转录因子，可以通过将特异性配体(即类固醇激素(SH))结合到配体结合结构域(LBD)而激活(Ray DW等，1999;派克等人，1999;Bledsoe RK et al. 2002;李毅等，2005;Kumar R和McEwan IJ 2012;Kumar R et al. 2011;Williams SP和Sigler PB 1998;Tanenbaum DM et al. 1998;Lusher SJ et al. 2012)。LBD (e区)位于受体的c端一半，除了配体结合功能外，还包含转录激活功能(AF2)，二聚化，热休克蛋白结合，分子间沉默和分子内抑制的序列(Kumar R和McEwan IJ 2012)。 The binding of hormone acts as an allosteric switch to regulate SHR-DNA and SHR-protein interactions, including interdomain interactions and/or dimerization (Kumar R and McEwan IJ 2012).SHs are synthesized from cholesterol in the adrenal cortex (glucocorticoids, mineralocorticoids, and adrenal androgens), the testes (testicular androgens, estrogen), and the ovary and placenta (estrogen and progestogen or progestins) (Payne AH and Hales DB 2004; Hu J et al. 2010;). SHs reach their target cells via the blood, where they are bound to specific carrier proteins (Grishkovskaya I et al. 2000; Hammond GL 2016). SHs detach from the carrier proteins and because of their lipophilic nature readily diffuse through the plasma membrane of cells (Oren I et al. 2004). Within the target cells SHs bind to steroid hormone receptors (SHRs) which are present in a heterocomplex with heat shock protein HSP90 and co-chaperones (e.g., immunophilins p23) (Echeverria PC and Picard D 2010). The ATP-bound form of HSP90 and chaperone-mediated conformational changes are required to keep SHRs in a ligand binding-competent state (McLaughlin SH et al. 2002; Pratt WB et al. 2008; Krukenberg KA et al. 2011).

皮质类固醇与糖皮质激素受体NR3C1结合(Rupprecht et al. 1993, Lind et al. 2000)，抑制促炎NF-Kappa B等炎症转录因子，促进白细胞介素-10等抗炎基因。皮质类固醇的短期作用是降低血管舒张和毛细血管的通透性，以及减少白细胞向炎症部位的迁移。从2020年6月的COVID-19治疗(恢复)随机评估试验中，地塞米松被推荐用于COVID-19严重呼吸道症状患者。在试验中，地塞米松将需要通气的患者的死亡率降低了约三分之一，将需要吸氧的患者的死亡率降低了五分之一。

类固醇激素受体(SHRs)是细胞内的转录因子，可以通过将特异性配体(即类固醇激素(SH))结合到配体结合结构域(LBD)而激活(Ray DW等，1999;派克等人，1999;Bledsoe RK et al. 2002;李毅等，2005;Kumar R和McEwan IJ 2012;Kumar R et al. 2011;Williams SP和Sigler PB 1998;Tanenbaum DM et al. 1998;Lusher SJ et al. 2012)。LBD (e区)位于受体的c端一半，除了配体结合功能外，还包含转录激活功能(AF2)，二聚化，热休克蛋白结合，分子间沉默和分子内抑制的序列(Kumar R和McEwan IJ 2012)。 The binding of hormone acts as an allosteric switch to regulate SHR-DNA and SHR-protein interactions, including interdomain interactions and/or dimerization (Kumar R and McEwan IJ 2012).SHs are synthesized from cholesterol in the adrenal cortex (glucocorticoids, mineralocorticoids, and adrenal androgens), the testes (testicular androgens, estrogen), and the ovary and placenta (estrogen and progestogen or progestins) (Payne AH and Hales DB 2004; Hu J et al. 2010;). SHs reach their target cells via the blood, where they are bound to specific carrier proteins (Grishkovskaya I et al. 2000; Hammond GL 2016). SHs detach from the carrier proteins and because of their lipophilic nature readily diffuse through the plasma membrane of cells (Oren I et al. 2004). Within the target cells SHs bind to steroid hormone receptors (SHRs) which are present in a heterocomplex with heat shock protein HSP90 and co-chaperones (e.g., immunophilins p23) (Echeverria PC and Picard D 2010). The ATP-bound form of HSP90 and chaperone-mediated conformational changes are required to keep SHRs in a ligand binding-competent state (McLaughlin SH et al. 2002; Pratt WB et al. 2008; Krukenberg KA et al. 2011).