Crystal structure of human serum albumin complexed with fatty acid reveals an asymmetric distribution of binding sites

Curry, Stephen; Mandelkow, Hendrik; Brick, P.; Franks, Nicholas P.

doi:10.1038/1869

Cited by 1,291 publications

(1,294 citation statements)

References 24 publications

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“…S5), there is approximately one (1.1 ± 0.3) free SLFA in the buffered solution. This is consistent with the fact that there are seven FA binding sites on HSA [9] and eight SLFAs are present.…”

Section: Binding Of Complex 5 In Presence Of Long-chain Fatty Acids: supporting

confidence: 90%

“…Among the blood proteins, human serum albumin (HSA) is the most abundant (~630 mM) and can serve as a transport vehicle for various compounds including fatty acids (FAs), bilirubin, steroids, metal ions, and various pharmaceuticals [8]. There are seven distinct binding sites on HSA for long-chain FAs (FA1 -FA7) distributed throughout the protein in an asymmetric way [8], of which FA2, FA4, and FA5 are the highest affinity sites, as indicated by crystallographic studies [9]. The principal regions of exogenous drug binding sites are located in hydrophobic pockets in subdomains IIA and IIIA (site I and site II, respectively according to the conventional view based on Sudlow's classification) [8,10], and in the recently identified binding pocket within subdomain IB (site III) which is considered as the third major binding site [11].…”

Section: Interaction Of Anticancer Metallodrugs With Proteins Is Of Cmentioning

confidence: 99%

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Investigation of the binding of cis/trans-[MCl4(1H-indazole)(NO)]− (M = Ru, Os) complexes to human serum albumin

Dömötör

Rathgeb

Kuhn

et al. 2016

Journal of Inorganic Biochemistry

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Overall binding affinity of sodium or indazolium cis/trans-[MCl 4 (1H-indazole)(NO)] (M = Ru,Os) complexes towards human serum albumin (HSA) and high molecular mass components of the blood serum was monitored by ultrafiltration. HSA was found to be mainly responsible for the binding of the studied ruthenium and osmium complexes. In other words, this protein can provide a depot for the compounds and can affect their biodistribution and transport processes. In order to elucidate the HSA binding sites tryptophan fluorescence quenching studies and displacement reactions with the established site markers warfarin and dansylglycine were performed. Conditional stability constants for the binding to sites I and II on HSA were computed showing that the studied ruthenium and osmium complexes are able to bind into both sites with moderately strong affinity (logK' = 4.4-5.1). Site I is slightly more favored over site II for all complexes. No significant differences in the HSA binding properties were found for these metal complexes demonstrating negligible influence of the type of counter ion (sodium vs. indazolium), the metal ion center identity (Ru vs. Os) or the position of the nitrosyl group on the binding 2 event. Electron paramagnetic resonance spin labeling of HSA revealed that indazolium trans-[RuCl 4 (1H-indazole)(NO)] and long-chain fatty acids show competitive binding to HSA.Moreover, this complex has a higher affinity for site I, but when present in excess, it is able to bind to site II as well, and displace fatty acids.

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Section: Binding Of Complex 5 In Presence Of Long-chain Fatty Acids: supporting

confidence: 90%

Section: Interaction Of Anticancer Metallodrugs With Proteins Is Of Cmentioning

confidence: 99%

Investigation of the binding of cis/trans-[MCl4(1H-indazole)(NO)]− (M = Ru, Os) complexes to human serum albumin

Dömötör

Rathgeb

Kuhn

et al. 2016

Journal of Inorganic Biochemistry

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“…Not much electron density was observed in the FA site 1 located in subdomain IB, consistent with the proposal that this site is a weak FA binding site. 13,14 In the FA site 6 and site 7 (Sudlow site I), the electron densities [ Fig. 2(A,B)] were much larger than what typically observed for myristate and were modeled with confidence to DAUDA molecules, which has a large dansyl head group compared with myristate.…”

Section: Reliability Of the Rhsa-myr-dauda Structurementioning

confidence: 95%

“…5,11,12 In addition, a total of seven major fatty acid (FA) binding sites in defatted HSA are also identified mainly through the extensive works by Curry. 6,13,14 These FA binding sites distributed across the protein and are available for the binding of exogenous compounds. FA sites 2, 4, and 5 on HSA were proposed to have the high affinity toward FA.…”

Section: Introductionmentioning

confidence: 99%

A fluorescent fatty acid probe, DAUDA, selectively displaces two myristates bound in human serum albumin

et al. 2011

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11-(Dansylamino) undecanoic acid (DAUDA) is a dansyl-type fluorophore and has widely used as a probe to determine the binding site for human serum albumin (HSA). Here, we reported that structure of HSA-Myristate-DAUDA ternary complex and identified clearly the presence of two DAUDA molecules at fatty acid (FA) binding site 6 and 7 of HSA, thus showing these two sites are weak FA binding sites. This result also show that DAUDA is an appropriate probe for FA site 6 and 7 on HSA as previous studied, but not a good probe of FA binding site 1 that is likely bilirubin binding site on HSA.

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“…Albumin reacts with nitric oxide to form a stable Snitrosothiol that has endothelium-derived relaxing factor-like properties (Keaney et al, 1993). Albumin also plays a crucial role in binding and transport of fatty acids (Curry et al, 1998). We have shown that albumin reduces ischemic brain swelling (Belayev et ).…”

Section: Part Ii: Neuroprotection --Moving From the Present Into The mentioning

confidence: 99%

Neuroprotection for ischemic stroke: Past, present and future

2008

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Neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection. Rigorously conducted experimental studies in animal models of brain ischemia provide incontrovertible proof-of-principle that high-grade protection of the ischemic brain is an achievable goal. Nonetheless, many agents have been brought to clinical trial without a sufficiently compelling evidence-based pre-clinical foundation. At this writing, around 160 clinical trials of neuroprotection for ischemic stroke have been initiated. Of the approximately 120 completed trials, two-thirds were smaller early-phase safetyfeasibility studies. The remaining one-third were typically larger (>200 subjects) phase II or III trials, but, disappointingly, only fewer than one-half of these administered neuroprotective therapy within the 4-6 hour therapeutic window within which efficacious neuroprotection is considered to be achievable. This fact alone helps to account for the abundance of "failed" trials.This review presents a close survey of the most extensively evaluated neuroprotective agents and classes and considers both the strengths and weakness of the pre-clinical evidence as well as the results and shortcomings of the clinical trials themselves. Among the agent-classes considered are calcium channel blockers; glutamate antagonists; GABA agonists; antioxidants/radical scavengers; phospholipid precursor; nitric oxide signal-transduction down-regulator; leukocyte inhibitors; hemodilution; and a miscellany of other agents. Among promising ongoing efforts, therapeutic hypothermia, high-dose human albumin therapy, and hyperacute magnesium therapy are considered in detail. The potential of combination therapies is highlighted. Issues of clinical-trial funding, the need for improved translational strategies and clinical-trial design, and "thinking outside the box" are emphasized. Part I: Neuroprotection -from Past to the PresentNeuroprotection for ischemic brain injury has emerged only recently as a topic of serious biomedical inquiry. A MEDLINE survey (PubMed, 2007) reveals virtually no publications on this topic until the early 1990's but a remarkable surge in publications over the past 10 years Correspondence and reprint requests to:

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Crystal structure of human serum albumin complexed with fatty acid reveals an asymmetric distribution of binding sites

Cited by 1,291 publications

References 24 publications

Investigation of the binding of cis/trans-[MCl4(1H-indazole)(NO)]− (M = Ru, Os) complexes to human serum albumin

Investigation of the binding of cis/trans-[MCl4(1H-indazole)(NO)]− (M = Ru, Os) complexes to human serum albumin

A fluorescent fatty acid probe, DAUDA, selectively displaces two myristates bound in human serum albumin

Neuroprotection for ischemic stroke: Past, present and future

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