Carboxylate Binding Modes in Zinc Proteins: A Theoretical Study

Ryde, Ulf

doi:10.1016/s0006-3495(99)77110-9

Cited by 125 publications

(144 citation statements)

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“…Table II also shows the bond lengths of the optimized structures of the model molecules. The optimized values of the coordination bonds of the various models are generally in agreement with the results derived from B3LYP at the double-basis set level (51). The bond distances obtained by EXAFS analysis compared with those obtained by the B3LYP calculation indicate that the Zn-O and Zn-N distances are in good agreement within the experimental error.…”

Section: Resultssupporting

confidence: 79%

Structural Characterization of the Catalytic Active Site in the Latent and Active Natural Gelatinase B from Human Neutrophils

Kleifeld¹,

Steen²,

Frenkel³

et al. 2000

Journal of Biological Chemistry

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Matrix metalloproteinases are endopeptidases that have a leading role in the catabolism of the macromolecular components of the extracellular matrix in a variety of normal and pathological processes. Human gelatinase B is a zinc-dependent proteinase and a member of the matrix metalloproteinase family that is involved in inflammation, tissue remodeling, and cancer. We have conducted x-ray absorption spectroscopy, atomic emission, and quantum mechanics studies of natural and activated human gelatinase B. Our results show that the natural enzyme contains one catalytic zinc ion that is central to catalysis. In addition, upon enzyme activation, the catalytic zinc site exhibits a conformation change that results in the expansion of the bond distances around the zinc ion and the replacement of one sulfur with oxygen. Interestingly, quantum mechanics calculations show that oxygen ligation at the catalytic zinc ion exhibits a greater affinity to the binding of an oxygen from an amino acid residue rather than from an external water molecule. These results suggest that the catalytic zinc ion plays a key role in both substrate binding and catalysis.Remodeling of the extracellular matrix is an important event in many normal and pathological processes such as growth, wound repair, tumor metastasis, and leukocyte mobilization in inflammation. A large family of zinc-dependent proteinases, the matrix metalloproteinases (MMPs), 1 is considered to be primarily responsible for this matrix catabolism (1-4). Details of their variety and substrate specificity are documented in several recent reviews (5-7). The MMPs consist of a large family of proteinases that share many common structural and functional elements. MMPs can be categorized based on amino acid sequence similarity, substrate specificity, and domain structure. They include collagenases, which cleave triple helical interstitial collagens; gelatinases, which cleave denatured collagen, elastin and type IV and V collagens; stromelysins, which mainly cleave proteoglycans; and membrane-type MMPs, which are associated with the activation of pro-MMPs (2, 3). In addition to these classical MMPs, other metalloproteinases, mainly with functions other than matrix catabolism, are being discovered at an increasing pace. All MMPs are synthesized as preproenzymes and are usually secreted as inactive pro-MMPs. The primary structure of each MMP is composed of some of the following domain motifs: a signal peptide, a propeptide, a catalytic domain that contains a zinc ion central to catalysis, a linker, a hemopexin-like domain, a fibronectin type II domain, a transmembrane region and a cytoplasmic domain (found in membrane-types 1-6), a furinrecognition sequence, and a vitronectin-like domain (7). Moreover, each member of the MMP family is characterized by a different domain composition, but contains a propeptide domain of about 80 amino acids with a conserved PRCGVPDV motive that ligates to the catalytic zinc ion via the cysteine residue to maintain the latency of the proenzyme (8, 9). The ca...

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Section: Resultssupporting

confidence: 79%

Structural Characterization of the Catalytic Active Site in the Latent and Active Natural Gelatinase B from Human Neutrophils

Kleifeld¹,

Steen²,

Frenkel³

et al. 2000

Journal of Biological Chemistry

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“…S4D). This shift can occur against a relatively low-energy barrier and may reflect reduction of Zn 2+ -positive charge during binding of the negatively charged epoxide oxygen of LTA 4 (17).…”

Section: Resultsmentioning

confidence: 99%

Capturing LTA ₄ hydrolase in action: Insights to the chemistry and dynamics of chemotactic LTB ₄ synthesis

Stsiapanava

Samuelsson

Haeggström

2017

Proc. Natl. Acad. Sci. U.S.A.

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Human leukotriene (LT) A 4 hydrolase/aminopeptidase (LTA 4 H) is a bifunctional enzyme that converts the highly unstable epoxide intermediate LTA 4 into LTB 4 , a potent leukocyte activating agent, while the aminopeptidase activity cleaves and inactivates the chemotactic tripeptide Pro-Gly-Pro. Here, we describe high-resolution crystal structures of LTA 4 H complexed with LTA 4 , providing the structural underpinnings of the enzyme's unique epoxide hydrolase (EH) activity, involving Zn 2+ , Y383, E271, D375, and two catalytic waters. The structures reveal that a single catalytic water is involved in both catalytic activities of LTA 4 H, alternating between epoxide ring opening and peptide bond hydrolysis, assisted by E271 and E296, respectively. Moreover, we have found two conformations of LTA 4 H, uncovering significant domain movements. The resulting structural alterations indicate that LTA 4 entrance into the active site is a dynamic process that includes rearrangement of three moving domains to provide fast and efficient alignment and processing of the substrate. Thus, the movement of one dynamic domain widens the active site entrance, while another domain acts like a lid, opening and closing access to the hydrophobic tunnel, which accommodates the aliphatic tale of LTA 4 during EH reaction. The enzyme-LTA 4 complex structures and dynamic domain movements provide critical insights for development of drugs targeting LTA 4 H. is a 69-kDa cytosolic bifunctional zinc metalloenzyme that converts the transient epoxide LTA 4 (5S-5,6-oxido-7,9-trans-11,14-cis-eicosatetraenoic acid) into the dihydroxy acid LTB 4 (5S,12R-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid) via a unique epoxide hydrolase (EH) reaction (1). LTB 4 , a potent chemotactic and immune-activating agent, is implicated in acute and chronic inflammatory diseases (2, 3), cardiovascular disorders (4, 5), and carcinogenesis (6). In addition to its proinflammatory EH activity, LTA 4 H may also counteract inflammation by its aminopeptidase activity, which inactivates by cleavage another neutrophil attractant, the tripeptide Pro-Gly-Pro (PGP) (7). In addition, the fatty acid epoxide LTA 4 is also the key precursor for biosynthesis of lipoxins, a family of anti-inflammatory, proresolving lipid mediators (8). Hence, LTA 4 H is a checkpoint in lipid mediator biosynthesis that regulates both the initiation and resolution phases of inflammation.LTA 4 H consists of N-terminal, catalytic, and C-terminal domains whose interface delimits a deep cleft harboring an L-shaped pocket, with a wide polar arm that binds PGP and a narrow hydrophobic arm that is believed to accommodate LTA 4 (9). The elbow of the pocket includes H295, H299, and E318, which coordinate a Zn 2+ ion essential for both LTA 4 H activities.LTA 4 H is the only EH reported to form a nonvicinal distant 5,12 diol (10), requiring an atypical catalytic mechanism, the details of which have remained elusive in the absence of a crystal structure with bound substrate (11). Acquirement of an enzymesubstr...

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“…We study how the hydrogen-bond strength depends on the type of metal and its oxidation state, the coordination number, the type of the ligand, other ligands of the metal, and on the nature of the second-sphere hydrogen-bond partner. We study over 60 different complexes, taken mainly from our previous theoretical studies of various metalloproteins [18,19,22,38,39,40,41,42,43,44,45,46,47]. The results provide much insight into how metal coordination affects the geometry and energy of hydrogen bonds to ligating…”

Section: Introductionmentioning

confidence: 99%

How are hydrogen bonds modified by metal binding?

Husberg

Ryde

2013

J Biol Inorg Chem

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How are hydrogen bonds modified by metal binding?Husberg, Charlotte; Ryde, Ulf General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. AbstractWe have used density-functional theory calculations to investigate how the hydrogenbond strength is modified when a ligand is bound to a metal, using over 60 model systems involving six metals and eight ligands frequently encountered in metalloproteins. We study how the hydrogen-bond geometry and energy vary with the nature of metal, the oxidation state, the coordination number, the ligand involved in the hydrogen bond, other first-sphere ligands, and different hydrogen-bond probe molecules. The results show that in general, the hydrogen-bond strength is increased for neutral ligands and decreased for negatively charged ligands. The size of the effect is mainly determined by the net charge of the metal complex and all effects are typically decreased when the model is solvated. In water solution, the hydrogen-bond strength can increase by up to 37 kJ/mol for neutral ligands, and that of negatively charged ligands can both increase (for complexes with a negative net charge) or decrease (for positively charged complexes). If the net charge of the complex does not change, there is normally little difference between different metals or different types of complexes. The only exception is observed for sulphur-containing ligands (Met and Cys) and if the ligand is redox active (e.g. high-valent Fe-O complexes).Key Words: hydrogen bonds, metalloproteins, quantum-mechanical calculations, densityfunctional theory, dispersion correction, solvation. 2 IntroductionHydrogen bonds play an important role in all types of biochemical systems, strongly affecting catalysis, ligand binding, and enzyme function, for example [1]. They have been thoroughly studied by a variety of experimental and theoretical methods [2,3,4,5,6,7,8,9,10,11,12,13,14,15] so that the strengths of the common hydrogen bonds in biological systems are accurately known.However, it is well-known that metal sites affect the properties of bound ligands. For example, the pK a value of water in aqueous metal complexes is reduced from 15.7 for bulk water, to 12.8 for Ca 2+ and to 2.2 for Fe 3+ [16]. Therefore, it is also likely that metal ions also change the strength and structure of hydrogen bonds inv...

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Carboxylate Binding Modes in Zinc Proteins: A Theoretical Study

Cited by 125 publications

References 40 publications

Structural Characterization of the Catalytic Active Site in the Latent and Active Natural Gelatinase B from Human Neutrophils

Structural Characterization of the Catalytic Active Site in the Latent and Active Natural Gelatinase B from Human Neutrophils

Capturing LTA ₄ hydrolase in action: Insights to the chemistry and dynamics of chemotactic LTB ₄ synthesis

How are hydrogen bonds modified by metal binding?

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Carboxylate Binding Modes in Zinc Proteins: A Theoretical Study

Cited by 125 publications

References 40 publications

Structural Characterization of the Catalytic Active Site in the Latent and Active Natural Gelatinase B from Human Neutrophils

Structural Characterization of the Catalytic Active Site in the Latent and Active Natural Gelatinase B from Human Neutrophils

Capturing LTA 4 hydrolase in action: Insights to the chemistry and dynamics of chemotactic LTB 4 synthesis

How are hydrogen bonds modified by metal binding?

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Capturing LTA ₄ hydrolase in action: Insights to the chemistry and dynamics of chemotactic LTB ₄ synthesis