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High-Resolution Neutron Structure of Nicotinamide Adenine Dinucleotide Benoît Guillot, Claude Lecomte, Alain Cousson, Christian Scherf, Christian Jelsch

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High-Resolution Neutron Structure of Nicotinamide Adenine Dinucleotide Benoît Guillot, Claude Lecomte, Alain Cousson, Christian Scherf, Christian Jelsch High-resolution neutron structure of nicotinamide adenine dinucleotide Benoît Guillot, Claude Lecomte, Alain Cousson, Christian Scherf, Christian Jelsch To cite this version: Benoît Guillot, Claude Lecomte, Alain Cousson, Christian Scherf, Christian Jelsch. High-resolution neutron structure of nicotinamide adenine dinucleotide. Acta Crystallographica Section D: Bi- ological Crystallography, International Union of Crystallography, 2001, D57 (7), pp.981-989. 10.1107/S0907444901007120. hal-01713037 HAL Id: hal-01713037 https://hal.archives-ouvertes.fr/hal-01713037 Submitted on 20 Feb 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. electronic reprint Acta Crystallographica Section D Biological Crystallography ISSN 0907-4449 High-resolution neutron structure of nicotinamide adenine dinucleotide Benoit Guillot, Claude Lecomte, Alain Cousson, Christian Scherf and Christian Jelsch Copyright © International Union of Crystallography Author(s) of this paper may load this reprint on their own web site provided that this cover page is retained. Republication of this article or its storage in electronic databases or the like is not permitted without prior permission in writing from the IUCr. + Acta Cryst. (2001). D57, 981–989 Guillot et al. ¯ Neutron structure of NAD research papers Acta Crystallographica Section D Biological High-resolution neutron structure of nicotinamide Crystallography adenine dinucleotide ISSN 0907-4449 Benoit Guillot,a Claude The structure of the free-acid form of the coenzyme NAD+ Received 26 February 2001 Lecomte,a Alain Cousson,b was determined at 100 K from a single-crystal neutron Accepted 27 April 2001 + Christian Scherfb,c and Christian experiment. NAD is the oxidized form of the coenzyme + Jelscha* redox pair NAD /NADH and plays an important role in the NDB Reference: NAD+, catalysis of biological processes. The molecule crystallizes in ur0013. space group P1 with one NAD+ and four water molecules per aLaboratoire de Cristallographie et de unit cell. The structure is compared with the previous X-ray ModeÂlisation des MateÂriaux MineÂraux et models of NAD+ [Reddy et al. (1981), J. Am. Chem. Soc. 103, Biologiques (LCM3B), CNRS ESA 7036, UHP Faculte des Sciences, BP 239, 54506 907±914; Parthasarathy & Fridey (1984b), Science, 226, 969± Vandoeuvre-les-Nancy CEDEX, France, 971; Guillot et al. (2000), Acta Cryst. C56, 726±728]. The crystal bLaboratoire LeÂon Brillouin (CEA±CNRS), CEA packing and the hydrogen-bond pattern are discussed as well Saclay, 91191 Gif-sur-Yvette CEDEX, France, as four short CÐH O contacts involving the pyridine and c and Institut fuÈr Kristallographie, RWTH Aachen, adenine rings. TheÁÁÁ structure displays stereochemical distor- 52056 Aachen, Germany tions owing to the hydrogen bonding and crystal-packing constraints, re¯ecting the adaptability of the NAD+ molecule Correspondence e-mail: in various chemical environments. [email protected] 1. Introduction The nicotinamide adenine dinucleotide cofactor (NAD+) plays a major role in enzyme-catalyzed biological oxido- reduction processes. NAD+ is the oxidized form of the redox pair NAD+/NADH and binds to enzymes involved in catabolic oxidative reactions, mostly dehydrogenases. As depicted in Fig. 1, the NAD+ molecule is composed of a pyrophosphate moiety linking an adenylic acid and a nicotinamide-50-ribo- nucleotide group together. In the dehydrogenation process, the NAD+ molecule is reduced to NADH by accepting a + hydride anion (H ,2e) from the substrate to its redox-active site located on the C18 atom (in the present paper nomen- clature) of the nicotinamide ring. The goal of this study was to determine accurately the position of the protons of the molecule as well as their anisotropic thermal displacement parameters, to be used in a further [X (X + N)] charge- density analysis. This structure is described and compared with the X-ray structure recently deposited at the Cambridge Structural Database (Guillot et al., 2000) and to the lithium dihydrate complex of NAD+ (Saenger et al., 1977; Reddy et al., 1981). 2. Experimental 2.1. Crystallization NAD+ was purchased in lyophilized form from Sigma (St Louis, USA). The crystallization solution was prepared in the following way: 1 g of NAD+ was dissolved in 1 ml puri®ed water. 50 ml LiOH (1 M) was then added to 100 ml of the # 2001 International Union of Crystallography solution. Finally, 200 ml methanol was slowly added to reduce + Printed in Denmark ± all rights reserved the solubility of NAD . The pH of the ®nal solution was about + Acta Cryst. (2001). D57, 981±989 Guillot et al. Neutron structure of NAD 981 electronic reprint research papers Table 1 was measured at 7.5 h intervals and showed no detectable Crystallographic data. decay. The data were corrected for Lorentz effects but not for 1 Radiation type Neutron absorption (est = 0.18 mm ) as the crystal was of small size Wavelength (AÊ ) 0.8305 (2) and cylindrical shape. The Friedel pairs were not averaged but Space group Triclinic P1 Z 1 an internal agreement factor calculated on the 353 measured F(000) (e) 384 Friedel equivalent re¯ections leads to Rmerge = 0.056. Unit-cell parameters a (AÊ ) 8.57 (1) b (AÊ ) 8.83 (1) 2.3. Neutron least-squares refinement Ê c (A) 11.19 (1) The initial coordinates were taken from the X-ray structure () 109.7 (1) + () 90.6 (1) of NAD (Guillot et al., 2000) and re®ned against the neutron- () 104.0 (1) diffraction data [I >3(I)] using the program MOPRO Ê Resolution (A) 0.65 ( 13 h 13, (Guillot et al., 2001). The re®nement was performed against 13 k 13, 17 l 1) the structure-factor moduli F , with a weighting scheme 2 j j No. of measured re¯ections 6343 w =1/F . Data-collection and re®nement statistics are given in No. of unique re¯ections 5990 Table 1. During the re®nement, all the atoms were re®ned No. of re¯ections with I/(I) > 3 4988 anisotropically without application of any restraint. There Rmerge(I)² 0.056 I/(I) were 249 positional and 498 thermal displacement re®ned h i All re¯ections 12.9 parameters, leading to a ratio of observations to variables of Highest resolution, d < 0.67 AÊ 6.5 Re¯ections with I/(I) > 3 (%) 6.7. To re®ne the structure, the following re®nement strategy All re¯ections 78 was applied: ®rst, all the thermal motion parameters and the Ê Highest resolution, d < 0.67 A 61 positions of all atoms except O1 were re®ned separately. The R (F)³ All re¯ections 0.095 positional and thermal motion parameters of all atoms of the I/(I) > 3 0.062 nicotinamide ribonucleotide were then re®ned together, the wR (F)§ other atoms remaining ®xed. The same procedure was applied All re¯ections 0.054 I/(I) > 3 0.050 to the atoms of the adenine side of the molecule and ®nally to GoF} the atoms of the pyrophosphate group. This method avoids the All re¯ections 1.95 problem of the ¯oating origin in space group P1, as some I/(I) > 3 2.00 heavy-atom coordinates are kept ®xed during each stage of 2 2 1=2 ² Rmerge(I)= Ph Pi wh;i Ih;i Ih / Ph Pi wh;i Ih;i .³R(F)= the re®nement. The whole procedure was cycled until total f 2 2h1=2 i h i g 2 Ph Fobs h Fcalc h /Ph Fobs h . § wR(F)= Ph w Fobs h Fcalc h / f j j2 1 j=2 j j j g f 2 j j 1= j2 j convergence, then a ®nal full normal matrix inversion with all Ph w Fobs h . } GoF = Ph w Fobs h Fcalc h / Nobs Npar : wh;i = j 2 j g f j j j j g 2 1= I ;i is the weighting factor for observation number i of the re¯ection h. w =1=F the atomic parameters except the O1 coordinates was h is the weighting factor of the unique re¯ection h. Nobs is the number of observations used performed to extract the standard uncertainties, parameter for the re®nement and Npar the number of re®ned parameters; Fobs are the scaled observed structure-factor amplitudes and Fcalc the calculated structure-factor ampli- correlation and to calculate the goodness of ®t (S). At the end tudes. of the re®nement, the statistical agreement factor Rw was 5.04% for re¯ections with I >3(I). The extinction (Lorenz, 3.5. Several identical batches were prepared, with crystals type I) was found to be very small, with a maximal value appearing in all of them after 48 h. One of the batches y = 0.917 for the (200) re¯ection. contained a 5.5 1.4 1.3 mm colourless crystal suitable for a neutron-diffraction experiment. 3. Results and discussion 2.2. Data collection 3.1. Comparison between neutron and X-ray structures The neutron-diffraction data were collected at cryogenic A view of the molecule with the atomic thermal ellipsoids is shown in Fig. 2. The distances between bonded atoms in temperature [100 (2) K] with a Stoe four-circle diffractometer + on the 5C2 channel at the LeÂon±Brilloin Laboratory facility NAD are given in Table 2 and selected torsion and angle (CNRS-CEA, Saclay, France). The 5C2 channel is at the end values in Table 3.
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