Very high resolution structure of a trematode hemoglobin displaying a TyrB10-TyrE7 heme distal residue pair and high oxygen affinity

Pesce, Alessandra; Dewilde, Sylvia; Kiger, Laurent; Milani, Mario; Ascenzi, Paolo; Marden, Michael C.; Hauwaert, M L Van; Vanfleteren, Jacques R.; Moëns, Luc; Bolognesi, Martino

doi:10.1006/jmbi.2001.4731

Cited by 45 publications

(90 citation statements)

References 56 publications

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“…Interaction of tyrosine with other amino acid side chains at the distal heme pocket probably contributes to such a drastic difference in ligand specificity. Similar affinity-changing interactions have been characterized for the Tyr-Glu pair in the distal heme pocket of globins (33,34) and the Tyr-Thr pair in the minihemoglobin of the nemertean worm Cerebratulus lacteus (35).…”

Section: Discussionsupporting

confidence: 54%

Ligand Selectivity of Soluble Guanylyl Cyclase

Martin

Berka²,

Bogatenkova

et al. 2006

Journal of Biological Chemistry

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Although soluble guanylyl cyclase (sGC) functions in an environment in which O 2 , NO, and CO are potential ligands for its heme moiety, the enzyme displays a high affinity for only its physiological ligand, NO, but has a limited affinity for CO and no affinity for O 2 . Recent studies of a truncated version of the sGC ␤ 1 -subunit containing the heme-binding domain (Boon, E. M., Huang, S H., and Marletta, M. A. (2005) Nat. Chem. Biol., 1, 53-59) showed that introduction of the hydrogen-bonding tyrosine into the distal heme pocket changes the ligand specificity of the heme moiety and results in an oxygen-binding sGC. The hypothesis that the absence of hydrogen-bonding residues in the distal heme pocket is sufficient to provide oxygen discrimination by sGC was put forward. We tested this hypothesis in a context of a complete sGC heterodimer containing both the intact ␣ 1 -and ␤ 1 -subunits. We found that the I145Y substitution in the full-length ␤-subunit of the sGC heterodimer did not produce an oxygen-binding enzyme. However, this substitution impeded the association of NO and destabilized the NO⅐heme complex. The tyrosine in the distal heme pocket also impeded both the binding and dissociation of the CO ligand. We propose that the mechanism of oxygen exclusion by sGC not only involves the lack of hydrogen bonding in the distal heme pocket, but also depends on structural elements from other domains of sGC. Soluble guanylyl cyclase (sGC)4 is a member of the guanylyl cyclase family of proteins, which respond to various ligands by converting GTP into cGMP. sGC stands apart from other members of its family by the nature of its activating ligand. Although other guanylyl cyclases are stimulated in response to various hormonal peptide ligands such as natriuretic peptides, guanylins, or toxins like heat-stable enterotoxin (see Ref. 1 for review), sGC is activated several hundredfold upon exposure to NO produced by nitric-oxide synthase. sGC is the key component of the NO/cGMP pathway and is crucial in mediating various physiological effects of NO such as blood vessel relaxation, inhibition of platelet aggregation, neurotransmission, and many others (2).The affinity of the sGC enzyme for NO is mediated by the ferrous heme prosthetic group. sGC possesses a ligand selectivity unique for hemeproteins. NO binds to the sGC heme at rates that are almost diffusion-limited (3) to form a stable NO⅐heme complex. High affinity coupled with high specificity for NO is essential for sGC to function as an NO receptor. Although sGC functions in the intracellular environment containing 20 -40 M O 2 and up to 10 nM NO during NO synthesis (4), sGC is capable of discriminating between these two similar molecules in favor of NO. Moreover, even in the absence of NO, sGC does not form an oxyferrous heme complex and does not show any significant autoxidation. This is especially interesting considering that, in some aspects, the sGC heme is similar to the heme moiety of globin oxygen carriers such as myoglobins and hemoglobins. Similar to globi...

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Section: Discussionsupporting

confidence: 54%

Ligand Selectivity of Soluble Guanylyl Cyclase

Martin

Berka²,

Bogatenkova

et al. 2006

Journal of Biological Chemistry

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“…Solution 1 H NMR of both metHbCN complexes exhibit (29, 30) a strongly relaxed and dipolar shifted labile proton, as shown in Figure 8 for Paraphistomum metHbCN (30). Magnetic axes determination showed the overall structure of metHbCN in solution to be the same as metHbH 2 O in the crystal (31). The plot of predicted d dip (calc) (Eq.…”

Section: Globinsmentioning

confidence: 87%

“…The monomeric Hbs from some nematodes/trematodes such as Ascaris suum (27), and Paraphistomum epiclitum, exhibit (28) extraordinarily slow O 2 off-rates and high O 2 affinities that have been attributed to very strong H-bond by an unusual Tyr(B10). While it has not been possible to obtain suitable crystals for HbO 2 , a crystal structure of Paraphistomum metHbH 2 O has been reported (31). Solution 1 H NMR of both metHbCN complexes exhibit (29, 30) a strongly relaxed and dipolar shifted labile proton, as shown in Figure 8 for Paraphistomum metHbCN (30).…”

Section: Globinsmentioning

confidence: 99%

Application of the paramagnetic dipole field for solution NMR active site structure determination in low‐spin, cyanide‐inhibited ferric hemoproteins

Mar¹

2007

IUBMB Life

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SummaryThe principles for the application of the paramagnetic dipolar field of low-spin, cyanide-inhibited ferrihemoproteins for determining active site structure are briefly described. The ubiquitous dipolar shifts for assigned residues, together with crystal coordinates of some appropriate structural homolog, allow determination of the orientation and anisotropies of the paramagnetic dipolar tensor. The orientation of w uniquely defines the orientation of the Fe-CN unit, which is tilted variably and sensitively monitors distal steric and H-bond interactions. The mapped dipolar field, in turn, can be used to determine the orientation of mutated residues. Case studies involving unusual genetic variants and point mutants of myoglobins, human hemoglobins, horseradish peroxidase and its substrate complex of heme oxygenase are presented as examples.IUBMB Life, 59: 513-527, 2007

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“…Crystal structures of three group I trHbs (2,3) revealed that trHbs are clearly not just another variation on the motif of vertebrate myoglobin (Mb) and Hb. Neither are they similar to nonvertebrate Hbs, including the heme-containing domain of flavohemoglobins, nor to the plant symbiotic and nonsymbiotic Hbs (4)(5)(6)(7)(8)(9)(10). Major structural differences associated with known trHbs are an unprecedented 2-on-2 ␣-helical sandwich fold, resulting from striking editing of the classical 3-on-3 globin ␣-helical sandwich, and an extended hydrophobic tunnel͞cavity network linking the solvent space and the distal heme pocket (1)(2)(3).…”

mentioning

confidence: 99%

“…The different H-bond networks thus achievable may not only stabilize the bound O 2 but also modulate the positioning and dynamics of distal pocket residues that participate in the control of ligand access to the iron, ligand diffusion within the distal heme pocket, and ligand diffusion into and out of the distal heme pocket (1)(2)(3)(4)(5)(6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

A TyrCD1/TrpG8 hydrogen bond network and a TyrB10—TyrCD1 covalent link shape the heme distal site of Mycobacterium tuberculosis hemoglobin O

Milani

Savard

Ouellet

et al. 2003

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

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109

158

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Truncated hemoglobins (Hbs) are small hemoproteins, identified in microorganisms and in some plants, forming a separate cluster within the Hb superfamily. Two distantly related truncated Hbs, trHbN and trHbO, are expressed at different developmental stages in Mycobacterium tuberculosis. Sequence analysis shows that the two proteins share 18% amino acid identities and belong to different groups within the truncated Hb cluster. Although a specific defense role against nitrosative stress has been ascribed to trHbN (expressed during the Mycobacterium stationary phase), no clear functions have been recognized for trHbO, which is expressed throughout the Mycobacterium growth phase. The 2.1-Å crystal structure of M. tuberculosis cyano-met trHbO shows that the protein assembles in a compact dodecamer. Six of the dodecamer subunits are characterized by a double conformation for their CD regions and, most notably, by a covalent bond linking the phenolic O atom of TyrB10 to the aromatic ring of TyrCD1, in the heme distal cavity. All 12 subunits display a cyanide ion bound to the heme Fe atom, stabilized by a tight hydrogen-bonded network based on the (globin very rare) TyrCD1 and TrpG8 residues. The small apolar AlaE7 residue leaves room for ligand access to the heme distal site through the conventional ''E7 path,'' as proposed for myoglobin. Different from trHbN, where a 20-Å protein matrix tunnel is held to sustain ligand diffusion to an otherwise inaccessible heme distal site, the topologically related region in trHbO hosts two protein matrix cavities.T runcated hemoglobins (trHbs) are a class of small oxygenbinding hemoproteins, dispersed in eubacteria, cyanobacteria, protozoa, and plants, recently recognized as a separate cluster within the hemoglobin (Hb) superfamily. On the basis of amino acid sequence analysis, three phylogenetic groups (groups I, II, and III) have been identified within the trHb family; some organisms contain genes from more than one group, suggesting different functions for trHbs belonging to the diverse groups (1). Crystal structures of three group I trHbs (2, 3) revealed that trHbs are clearly not just another variation on the motif of vertebrate myoglobin (Mb) and Hb. Neither are they similar to nonvertebrate Hbs, including the heme-containing domain of flavohemoglobins, nor to the plant symbiotic and nonsymbiotic Hbs (4-10). Major structural differences associated with known trHbs are an unprecedented 2-on-2 ␣-helical sandwich fold, resulting from striking editing of the classical 3-on-3 globin ␣-helical sandwich, and an extended hydrophobic tunnel͞cavity network linking the solvent space and the distal heme pocket (1-3). Much smaller and topologically unrelated cavities, known by their ability to incorporate Xe atoms, have been found in Mb and interpreted as temporary ligand-docking sites (11,12). In trHbs, the positioning and size of the hydrophobic tunnel suggest important roles in controlling ligand access to the heme, in ligand storage, and͞or accumulation (1-3).An additional major diffe...

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Very high resolution structure of a trematode hemoglobin displaying a TyrB10-TyrE7 heme distal residue pair and high oxygen affinity

Cited by 45 publications

References 56 publications

Ligand Selectivity of Soluble Guanylyl Cyclase

Ligand Selectivity of Soluble Guanylyl Cyclase

Application of the paramagnetic dipole field for solution NMR active site structure determination in low‐spin, cyanide‐inhibited ferric hemoproteins

A TyrCD1/TrpG8 hydrogen bond network and a TyrB10—TyrCD1 covalent link shape the heme distal site of Mycobacterium tuberculosis hemoglobin O

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