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CETP是一種將血液中“好”脂肪轉(zhuǎn)化為“壞”脂肪的蛋白質(zhì),?？茖W(xué)家們在2007年2月號的《自然—結(jié)構(gòu)和分子生物學(xué)》期刊上報告說,，他們確定出了CETP的結(jié)構(gòu),。

脂蛋白質(zhì)有好幾種類型,，包括被稱為“壞”膽固醇的低密度脂蛋白質(zhì)（LDL）和被稱為“好”膽固醇的高密度脂蛋白質(zhì)（HDL）,。而CETP的功能就是將高密度蛋白質(zhì)轉(zhuǎn)化為低密度脂蛋白質(zhì)。

利用X射線結(jié)晶技術(shù),，Xiayang Qiu和同事發(fā)現(xiàn)CETP的形狀像一個中間有轉(zhuǎn)動隧道穿過的飛鏢,。曲率對擁有互補(bǔ)形狀的脂蛋白質(zhì)的靠近很重要。他們在隧道中發(fā)現(xiàn)了脂蛋白質(zhì),，而當(dāng)隧道被堵著時,，脂蛋白質(zhì)的轉(zhuǎn)化受到了影響，表明隧道是作為脂蛋白質(zhì)的出入口而存在的,。

因為CETP能將“好”膽固醇轉(zhuǎn)化為“壞”膽固醇,，能夠干擾這種活動的藥物可用于治療心血疾病的

英文原文：

Crystal structure of CETP: new hopes for raising HDL to decrease risk of cardiovascular disease?
James A Hamilton1 & Richard J Deckelbaum2

1 James A. Hamilton is in the Department of Physiology and Biophysics, Boston University School of Medicine, 715 Albany St., Boston, Massachusetts 02118-2526, USA

2 Richard J. Deckelbaum is in the Institute of Human Nutrition, Columbia University Medical Center, 630 W. 168th St., New York, New York 10032, USA. [email protected]

With the well-documented successes of statins in lowering the concentration of 'bad' cholesterol (found mainly in low-density lipoprotein, or LDL) in human plasma and in diminishing cardiovascular disease (CVD), there is increasing effort to develop drugs to raise 'good' cholesterol (in HDL). This task has proven to be difficult, and the human plasma protein CETP is a viable target for favorably altering cholesterol distribution among lipoproteins.

CETP, a 476-residue glycoprotein, facilitates the transfer of completely water-insoluble lipids between the lipoproteins that transport them through aqueous plasma. The lipoprotein structural organization is designed to shield these lipids (cholesteryl esters and triglycerides) from water by encapsulating them within a coating of polar lipids (mainly phospholipids) and proteins (Fig. 1)1, yet the core lipids can move between lipoprotein particles. First described as a 'high–molecular weight globulin' that stimulated transfer of cholesteryl ester between lipoproteins in the plasma of hypercholesterolemic rabbits2, CETP was subsequently shown to also transfer triglyceride and phospholipids3. The exchanges occur on a much faster timescale than does catabolism of the lipoproteins, leading to changes in composition while the lipoproteins are still in circulation4.

Figure 1. Hypothetical scheme of CETP transfer of cholesteryl ester (CE) and triglyceride (TG) between HDL and triglyceride-rich lipoproteins.

( 生物谷配圖)
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CETP in plasma (middle) is depicted with its concave surface and tunnel openings facing the reader. Top, CETP binds triglyceride-rich lipoprotein, exchanging phospholipid into the protein surface and extracting triglyceride from the lipoprotein monolayer12 into the CETP hydrophobic tunnel. Bottom, CETP binds cholesteryl ester–rich lipoprotein (HDL), exchanging phospholipid into the protein surface and extracting cholesteryl ester from the lipoprotein monolayer12 into the CETP hydrophobic tunnel. CETP can accommodate different-sized spherical lipoproteins on its concave surface by changing its own curvature.

Knowledge of the structure of CETP is vital for understanding how CETP interacts with lipoproteins, which include LDL as well as HDL, very-low-density lipoprotein (VLDL) and chylomicrons5. In the absence of the crystal structure, the binding interactions were inevitably described in general terms—for example, as comprised of both electrostatic and hydrophobic components6. Circular dichroism measurements of the secondary structure revealed similarities to BPI, a bacterial lipid-binding protein7, 8. The shape of CETP was described as 'elongated', and it was speculated that CETP might contain a curved surface similar to that in BPI, which would be compatible with the surface curvature of HDL8. A detailed model based on the known structure of BPI and on sequence alignments predicted a very close resemblance of the structures of the two proteins9.

The report by Qiu et al.10 on page 106 of this issue replaces the lower-resolution and speculative descriptions of CETP structural features with exceptional detail gleaned from the 2.2-Å crystal structure. As the transfer of insoluble lipids through an aqueous phase is an unusual biophysical event, it is not surprising that CETP has an elegant structure with some unique characteristics. The most unusual structural feature is a long (60 Å) continuous tunnel with a very large volume (2,560 Å3). The investigators were fortunate that the expressed protein contained bound lipids (cholesteryl ester and phospholipid) that are the natural ligands for CETP. Two cholesteryl ester molecules are located in the middle of the tunnel, which is lined with hydrophobic amino acid side chains. The small openings at each end of the tunnel are plugged by phospholipids with their acyl chains buried in the hydrophobic tunnel and their polar head groups localized at the aqueous interface. In contrast to other lipid-binding proteins, such as the intracellular fatty acid–binding proteins11, there is no flap over the binding pocket. The protein has an overall 'boomerang' shape and a fold with two barrels connected by a central -sheet that is similar to BPI, as predicted9, but the relative orientation of the domains differs from BPI.

The high-resolution structure permits new and less speculative hypotheses about the molecular mechanism of lipid transfer, as formulated by the authors. The radius of curvature in the CETP crystal would permit a very snug fit to the surface of HDL without substantial conformational change. Electrostatic interactions of the polar groups of the phospholipid bound to CETP with components of the HDL surface, presumably protein amino acid side chains, initiate transfer of the phospholipids to HDL. As the phospholipid acyl chains exit the underlying hydrophobic pocket in CETP, the cholesteryl ester or triglyceride bound to CETP probably fills this volume before water enters to create an energy barrier for transfer to HDL. Similarly, as the bound lipids leave CETP, they can be replaced by other lipids diffusing out of the surface of the lipoprotein (Fig. 1), possibly at the other end of the tunnel. Although cholesteryl ester and triglyceride are mainly encapsulated in a large oily core, they can partition to a small extent into the phospholipid-protein surface12, where CETP can bind the predominant species, namely cholesteryl ester in HDL and triglyceride in VLDL. The authors further hypothesize that cholesteryl ester and triglyceride pass completely through the tunnel, which at its narrowest point is substantially wider than the minimal cross-sectional area of cholesteryl ester or triglyceride.

The ability of CETP to facilitate bidirectional transfer of cholesteryl ester and triglyceride among plasma lipoproteins in humans provided an early understanding of the relationship of high plasma triglyceride and low HDL cholesterol levels13, each considered to be risk factors for CVD. Thus, there has been great interest in developing and testing drugs that would inhibit CETP. One such drug, torcetrapib, seemed particularly promising.

Torcetrapib has one high-affinity site on CETP and blocks transfer of lipids from CETP, even though it increases binding of this protein to HDL by five-fold8. In clinical trials, it had impressive HDL-raising properties and increased HDL particle size, and thus was predicted to lower CVD morbidity and mortality14. A newly published clinical trail has revealed high efficacy of torcetrapib administered with atorvstatin and no safety issues, except for small increases in blood pressure in some subjects15. However, as reported in the New York Times in an article entitled "End of drug trial is a big loss for Pfizer and heart patients,"16 a large phase III clinical trial was recently halted when early analyses found higher mortality rates of post–cardiac event heart patients receiving torcetrapib. The molecular explanations for this unexpected result are not clear. Perhaps increased binding of torcetrapib–CETP complexes to HDL interferes with some of the anti-CVD activity of HDL, such as its anti-inflammatory or antioxidant properties17. Another potential danger of lowering CETP activity in humans is that subjects with genetic loss-of-function polymorphisms for CETP not only have lower levels of plasma CETP but show increased CVD mortality in some studies, despite higher plasma levels of HDL18. As these subjects have larger HDL particle sizes, it is possible that uncharacterized properties of their abnormally large HDLs might bring adverse CVD effects. However, studies of other human genetic variants have suggested that decreased CETP activity is associated with decreased risk of CVD19. Furthermore, plasma HDL consists of a mixture of several particle sizes and compositions, and these show differential responses to statins19.

It is somewhat ironic that just as the torcetrapib trials were terminated, scientists from the same pharmaceutical company finalized the structure of CETP. This high-resolution structure breathes new life into the strategy of modulating CETP activity. It will permit design of new drugs and redesign of old drugs, perhaps including torcetrapib. If the failure of torcetrapib is related to its property of increasing CETP binding to HDL, knowledge of the CETP structure should aid in the design of a drug that effectively blocks CETP transfer activity without strong binding to HDL and potentially undesired modifications of its structure.

The crystal structure of CETP provides new evidence for the proposed mechanism of CETP action, as well as a basis for drug design. The preponderance of current evidence indicates that decreasing CETP-mediated transfer of cholesteryl ester from HDL is a sound strategy for lowering the risk of CVD. However, the total concentration of HDL cholesterol in the plasma is one marker for CVD, and the quality of HDL may be as important as its concentration. Furthermore, the clinical goal of targeting CETP activity in human plasma is to decrease atherosclerosis and the vulnerability of plaques to rupture. Future testing of pharmaceuticals will be enhanced by newly developed imaging methods such as serial magnetic resonance imaging of progression and regression of atherosclerotic plaques in live mice20 and imaging of plaque rupture in a rabbit model of atherothrombosis21. The human carotid artery is readily accessible to in vivo magnetic resonance imaging, which can detect changes not only in plaque volume but in plaque composition22. This technique thus represents another new valuable approach to test an endpoint of CETP inhibition.

REFERENCES

• BY-D-I經(jīng)皮黃疸儀	• 衛(wèi)生部：先看病后付費(fèi)不宜推行
• 控費(fèi)失當(dāng)危及醫(yī)保制度根在公立醫(yī)院改革	• 公立醫(yī)院改革將如何影響醫(yī)療器械產(chǎn)業(yè)？
• 醫(yī)改持續(xù)深化影響漸顯藥品流通業(yè)利潤增幅下滑	• 三明醫(yī)改三回歸：砍掉虛高抹掉灰色
• 黃潔夫：改善醫(yī)療生態(tài)環(huán)境是醫(yī)改成功的關(guān)鍵	• 陳仲強(qiáng)委員：發(fā)展社會辦醫(yī)先要卸包袱
• 從常用藥品短缺現(xiàn)象談醫(yī)藥價格改革	• 回眸2012年新醫(yī)改—邁向病有所醫(yī)新時代

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