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PubMed1996

ABGEN: a knowledge-based automated approach for antibody structure modeling.

Immunoglobulin (Ig) amino acid sequences are highly conserved and often have sequence homology ranging from 70 to 95%. Antigen binding fragments (Fab), variable region fragments (Fv), and single chain Fv (scFv) of more than 50 myeloma proteins and monoclonal antibodies (mAb) have been crystallized and display a high degree of structural similarity. Based on this observation, several homology modeling approaches have been developed for the prediction of Fab and Fv structures prior to their experimental determination. We have extracted features from existing Ig sequences, 44 known Fab and Fv structures to create an automated AntiBody structure GENeration (ABGEN) algorithm for obtaining structural models of antibody fragments. ABGEN utilizes a homology based scaffolding technique, and includes the use of invariant and strictly conserved residues, structural motifs of known Fab, canonical features of hypervariable loops, torsional constraints for residue replacements and key inter-residue interactions. The validity of the ABGEN algorithm has been tested using a five-fold cross validation with the existing Fab structures. Molecular mechanics and dynamics methods have been implemented with ABGEN models to accurately predict two Fab structures of anti-sweetener antibodies prior to crystallographic determinations.

Algorithms↗

PubMed1991

Manganese superoxide dismutase from Thermus thermophilus. A structural model refined at 1.8 A resolution.

The structure of Mn(III) superoxide dismutase (Mn(III)SOD) from Thermus thermophilus, a tetramer of chains 203 residues in length, has been refined by restrained least-squares methods. The R-factor [formula: see text] for the 54,056 unique reflections measured between 10.0 and 1.8 A (96% of all possible reflections) is 0.176 for a model comprising the protein dimer and 180 bound solvents, the asymmetric unit of the P4(1)2(1)2 cell. The monomer chain forms two domains as determined by distance plots: the N-terminal domain is dominated by two long antiparallel helices (residues 21 to 45 and 69 to 89) and the C-terminal domain (residues 100 to 203) is an alpha + beta structure including a three-stranded sheet. Features that may be important for the folding and function of this MnSOD include: (1) a cis-proline in a turn preceding the first long helix; (2) a residue inserted at position 30 that distorts the helix near the first Mn ligand; and (3) the locations of glycine and proline residues in the domain connector (residues 92 to 99) and in the vicinity of the short cross connection (residues 150 to 159) that links two strands of the beta-sheet. Domain-domain contacts include salt bridges between arginine residues and acidic side chains, an extensive hydrophobic interface, and at least ten hydrogen-bonded interactions. The tetramer possesses 222 symmetry but is held together by only two types of interfaces. The dimer interface at the non-crystallographic dyad is extensive (1000 A2 buried surface/monomer) and incorporates 17 trapped or structural solvents. The dimer interface at the crystallographic dyad buries fewer residues (750 A2/monomer) and resembles a snap fastener in which a type I turn thrusts into a hydrophobic basket formed by a ring of helices in the opposing chain. Each of the metal sites is fully occupied, with the Mn(III) five-co-ordinate in trigonal bipyramidal geometry. One of the axial ligands is solvent; the four protein ligands are His28, His83, Asp166 and His170. Surrounding the metal-ligand cluster is a shell of predominantly hydrophobic residues from both chains of the asymmetric unit (Phe86A, Trp87A, Trp132A, Trp168A, Tyr183A, Tyr172B, Tyr173B), and both chains collaborate in the formation of a solvent-lined channel that terminates at Tyr36 and His32 near the metal ion and is presumed to be the path by which substrate or other inner-sphere ligands reach the metal.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

PubMed1995

Model structure of the Omp alpha rod, a parallel four-stranded coiled coil from the hyperthermophilic eubacterium Thermotoga maritima.

Omp alpha is an outer-membrane protein that spans the periplasmic space of the hyperthermophilic eubacterium Thermotoga maritima. The molecule contains a globular head with an apparent diameter of 8 nm and a rod-shaped tail of 40 nm length. The sequence of the globular domain is homologous to a conserved region of cell wall-bound proteins and probably attaches Omp alpha to the peptidoglycan. The sequence of the rod domain resembles that of coiled coil proteins and ends in a transmembrane segment that anchors Omp alpha to the outer membrane. We have analysed Omp alpha by scanning transmission electron microscopy (STEM) and by statistical sequence analysis methods. The Omp alpha rod is a tetramer with an unusual periodicity of hydrophobic residues close to 3.6 that differs from the 3.5 periodicity of canonical coiled coils. This is due to periodic omissions of three residues in the heptad repeat pattern ("stutters") whose effect is to locally distort the packing of hydrophobic layers in the core of the coiled coil. Residues in position alpha are shifted to occupy a position halfway between positions alpha and d (x layers) and residues in positions d and e are shifted so that both participate in core packing interactions (da layers). Such distorted layers are frequently found in helical bundles and are characteristic of helices that do not undergo supercoiling. The only homo-oligomeric coiled coil of known structure which contains x and da layers is the three-stranded coiled coil of influenza haemagglutinin. Using geometric constraints derived from this structure, we have built a model for the Omp alpha rod in which the helices have a crossing angle of less than 15 degrees and maintain a residual degree of supercoiling with a pitch of approximately 40 nm. Our analysis of distorted layers in the hydrophobic core of coiled coils and helical bundles shows that stutters must not be viewed as discontinuities but rather as a departure from the canonical "knobs-into-holes" packing that allows helices to interact at a low angle without supercoiling. Although stutters have been considered to weaken helical interactions, their occurrence in a rigid, highly thermostable coiled coil indicates that this may not be generally true. Our analysis also indicates that skips and stutters are two different conventions for describing the same underlying structural feature.

Amino Acid Sequence↗

PubMed2004

Computational analysis of alpha-helical membrane protein structure: implications for the prediction of 3D structural models.

Relatively little has been known about the structure of alpha-helical membrane proteins, since until recently few structures had been crystallized. These limited data have restricted structural analyses to the prediction of secondary structure, rather than tertiary folds. In order to address this, this paper describes an analysis of the 23 available membrane protein structures. A number of findings are made that are of particular relevance to transmembrane helix packing: (1) on average lipid-tail-accessible transmembrane residues are significantly more hydrophobic, less conserved and contain different residue types to buried residues; (2) charged residues are not always buried and, when accessible to membrane lipid tails, few are paired with another charge and instead they often interact with phospholipid head-groups or with other residue types; (3) a significant proportion of lipid-tail-accessible charged and polar residues form hydrogen bonds only with residues one turn away in the same helix (intra-helix); (4) pore-lining residues are usually hydrophobic and it is difficult to distinguish them from buried residues in terms of either residue type or conservation; and (5) information was gained about the proportion of helices that tend to contribute to lining a pore and the resulting pore diameter. These findings are discussed with relevance to the prediction of membrane protein 3D structure.

Databases, Protein↗

PubMed1994

Structural model for the reaction mechanism of glutamine synthetase, based on five crystal structures of enzyme-substrate complexes.

Glutamine synthetase brings nitrogen into metabolism by condensing ammonia and glutamate, with the aid of ATP, to yield glutamine, ADP, and inorganic phosphate. Here we present five crystal structures of GS complexed with each of two substrates, Glu and AMPPNP (an ATP analog), with a transition-state analogue, L-methionine-S-sulfoximine, and with each of two products, Gln and ADP. GS of the present study is from Salmonella typhimurium, has Mn2+ bound, and is fully unadenylylated. Protein-metal-substrate interactions and small but significant conformational changes induced by substrate binding are defined by Fourier maps. On the basis of these maps, we propose a tentative structure-based enzymatic mechanism of glutamine synthesis with these steps: (1) ATP binds first at the top of the funnel-shaped active site cavity, adjacent to the n2 Mn2+; Arg 359 moves toward the Glu binding site. (2) Glu binds adjacent to the n1 Mn2+ at the bottom of the active site near a flexible loop (residues 324-328). As proposed earlier by Meister and others, Glu attacks the gamma-phosphorus atom of ATP to produce gamma-glutamyl phosphate and ADP. (3) The presence of ADP (but not ATP) moves Arg 339 toward the Pi site, perhaps stabilizing the gamma-glutamyl phosphate, and moves Asp 50' of the adjacent subunit toward a putative ammonium ion site, enhancing binding of this third substrate. Deprotonation of the ammonium ion, perhaps by Asp 50', permits the resulting active species, ammonia, to attack the gamma-glutamyl phosphate, forming a tetrahedral intermediate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Imidodiphosphate↗

PubMed1998

Copper(II) Complexes with Unusual Axial Phenolate Coordination as Structural Models for the Active Site in Galactose Oxidase: X-ray Crystal Structures and Spectral and Redox Properties of [Cu(bpnp)X] Complexes.

The crystal structures of [Cu(bpnp)(SCN)].NH(4)SCN (1), [Cu(bpnp)(CH(3)COO)].CH(3)OH.C(8)H(10) (2), and [Cu(bpnp)ClO(4)] (3) [Hbpnp = 2-(bis(pyrid-2-ylmethyl)aminomethyl)-4-nitrophenol] reveal a distorted square pyramidal geometry around Cu(II) with an unusual axial coordination of phenolate. The mononuclear complex [Cu(bpnp)(SCN)].NH(4)SCN crystallizes in the triclinic space group P&onemacr; with a = 10.796(2) Å, b = 10.804(2) Å, c = 12.559(2) Å, alpha = 71.38(1) degrees, beta = 72.68(1) degrees, gamma = 61.69(1) degrees, and Z = 2. The mononuclear acetate [Cu(bpnp)(CH(3)COO)].CH(3)OH.C(8)H(10) crystallizes in the triclinic space group P&onemacr; with a = 10.480(6) Å, b = 12.116(4) Å, c = 12.547(3) Å, alpha = 98.77(3) degrees, beta = 113.37(3) degrees, gamma = 100.78(3) degrees, and Z = 2. The binuclear perchlorate complex crystallizes in the monoclinic space group C2/c with a = 13.417(3) Å, b = 20.095(2) Å, c= 16.401(2) Å, alpha = 102.21(2) degrees, and Z = 8. The coordination plane in all these complexes is comprised of the tertiary amine and two pyridine nitrogens. The fourth equatorial position is occupied by SCN(-)/CH(3)COO(-) in the mononuclear complexes but by the coordinated phenolate ion from the adjacent molecule in the perchlorate complex, resulting in its dimerization. The unusual occupation of phenolate ion in the axial site is possibly due to the steric constraint at copper imposed by the 5,5,6-chelate ring sequence. The thiocyanate/acetate coordination geometry is reminiscent of the active site of the radical copper enzyme galactose oxidase (GOase) with an axial phenolate and equatorial SCN(-)/CH(3)COO(-) ligands. Further, the present complexes exhibit several spectral features also similar to this enzyme. The addition of chloride or thiocyanate or acetate ions dissociates the dimeric structure of the perchlorate complex to produce the corresponding monomeric derivatives. The study of the interaction of the acetate complex with N(3)(-) and CN(-) ions provide insight into the anion binding properties of the enzyme. The sensitivity of the acetate complex to protons suggests the facile dissociation of the axial phenolate which then acts as a base to bind to protons. The implication of this reaction to the GOase mechanism is discussed.

Journal Article↗

PubMed1986

A common structural model for central nervous system drugs and their receptors.

On the basis of the hypothesis that there is a common structural basis for central nervous system (CNS) drug action consisting primarily of an aromatic group and a nitrogen atom, a four-point model for a common pharmacophore is defined with use of five semirigid CNS-active drug molecules: morphine, strychnine, LSD, apomorphine, and mianserin. Two of the points of the model represent possible hydrophobic interactions between the aromatic group and the receptor, while the other two represent hydrogen bonding between the nitrogen atom and the receptor. The model is then extended by the inclusion of nine additional CNS-active drug molecules: phenobarbitone, clonidine, diazepam, bicuculline, diphenylhydantoin, amphetamine, imipramine, chlorpromazine, and procyclidine, each being chosen as a key representative of a different CNS-active drug class or neurotransmitter system. Consideration of all phenyl group and nitrogen atom combinations, as well as all feasible conformations, shows that all nine molecules closely fit the common model in low-energy conformations. It is proposed that the model may eventually be used to design CNS-active drugs by mapping the relative locations of secondary binding sites. It can also be used to predict whether a given structure is likely to show CNS activity: a search over 1000 entries in the Merck Index shows a high probability of CNS activity in compounds fitting the common structural model.

Amphetamine↗

PubMed2002

A structural model for the catalytic cycle of Ca(2+)-ATPase.

Ca(2+)-ATPase is responsible for active transport of calcium ions across the sarcoplasmic reticulum membrane. This coupling involves an ordered sequence of reversible reactions occurring alternately at the ATP site within the cytoplasmic domains, or at the calcium transport sites within the transmembrane domain. These two sites are separated by a large distance and conformational changes have long been postulated to play an important role in their coordination. To characterize the nature of these conformational changes, we have built atomic models for two reaction intermediates and postulated the mechanisms governing the large structural changes. One model is based on fitting the X-ray crystallographic structure of Ca(2+)-ATPase in the E1 state to a new 6 A structure by cryoelectron microscopy in the E2 state. This fit indicates that calcium binding induces enormous movements of all three cytoplasmic domains as well as significant changes in several transmembrane helices. We found that fluorescein isothiocyanate displaced a decavanadate molecule normally located at the intersection of the three cytoplasmic domains, but did not affect their juxtaposition; this result indicates that our model likely reflects a native E2 conformation and not an artifact of decavanadate binding. To explain the dramatic structural effect of calcium binding, we propose that M4 and M5 transmembrane helices are responsive to calcium binding and directly induce rotation of the phosphorylation domain. Furthermore, we hypothesize that both the nucleotide-binding and beta-sheet domains are highly mobile and driven by Brownian motion to elicit phosphoenzyme formation and calcium transport, respectively. If so, the reaction cycle of Ca(2+)-ATPase would have elements of a Brownian ratchet, where the chemical reactions of ATP hydrolysis are used to direct the random thermal oscillations of an innately flexible molecule.

Adenosine Triphosphate↗

PubMed2004

Homology-modeled structure of the yeast mitochondrial citrate transport protein.

We have used homology modeling to construct a three-dimensional model of the yeast mitochondrial citrate transport protein (CTP), based on the recently published x-ray crystal structure of another mitochondrial transport protein, the ADP/ATP carrier. Superposition of the backbone traces of the homology-modeled CTP onto the crystallographically determined ADP carrier structure indicates that the CTP transmembrane domains are well modeled (i.e., root mean square deviation of 0.94 A), whereas the loops facing the intermembrane space and the mitochondrial matrix are less certain (i.e., root mean square deviation values of 0.72-2.06 A). The homology-modeled CTP is consistent with our earlier de novo models of the transporter's transmembrane domains, with respect to residues which face into the transport path. Importantly, the resulting model is consistent with our previous experimental data obtained from measuring reactivity of 34 single cysteine mutants in transmembrane domains 3 and 4 with methanethiosulfonate reagents. The model also points to a likely dimer interface region. In conclusion, our data help to define the substrate translocation pathway in both the modeled CTP structure and the crystallographic ADP carrier structure.

Amino Acid Sequence↗

PubMed1985

Structural model of the collagen-like region of C1q comprising the kink region and the fibre-like packing of the six triple helices.

A detailed three-dimensional model of the collagenous part of C1q was derived by model building and computer-aided energy refinement calculations. The proposed structure is based on the collagen-like (-Gly-Xaa-Yaa-) repeating sequence of 78 to 81 residues in the N-terminal regions of the constituent A, B and C chains, on the mode of disulphide linkage between the 18 chains of C1q, and on its electron microscopically derived gross structure. It is demonstrated that the interruptions of the repeating sequence about half-way along the length of the collagenous regions (Gly36-Ile37-Arg38-Thr39 in the A chain and Ala36-Ile37-Hy138 in the C chain) do not lead to a disruption of the triple helical conformation but rather to a bend of about 60 degrees in an otherwise continuous triple helix. These features are consistent with a flexibility comparable with that of regular triple helices and with the observed low proteolytic susceptibility of the kink region. The azimuthal orientation of the kink is defined approximately by ArgA38 being located in the cap of the knee. Because of this extra residue between two glycine residues, a bad contact that would arise between the methyl group of AlaC36 and the peptide carbonyl of IleA37 in a straight triple helix is relaxed. The model features also a cluster of hydrophobic contacts between large hydrophobic side-chains in the interaction edges between the six collagen triple helices aligned with their about 10 nm long N-terminal regions in the fibril-like endpiece of C1q. The azimuthal orientations of the triple helices were derived by energy calculations of side-chain interactions previously applied to fibre-forming collagens. Independently, the same orientations and interaction edges were derived from the azimuthal orientation of the kink and the electron microscopically observed orientations of the triple helical arms that emerge from the endpiece, and which carry the C-terminal globular binding domains. The structural model has a number of implications for the assembly of the first component of complement from C1q and the zymogen complex C1r2C1s2 and possible mechanisms of its activation.

Amino Acid Sequence↗

PubMed1999

Computationally derived structural models of the beta-amyloid found in Alzheimer's disease plaques and the interaction with possible aggregation inhibitors.

We report the modeling of and possible interactions within the solid beta-amyloid (ABeta) 1-43 fibril, the most fibrillogenic peptide known. All models proposed are consistent with the known experimental structural data, in terms of both secondary structure and packing motifs. The model containing antiparallel beta-sheets, and a beta-turn at G(25)S(26)N(27)K(28) has the lowest calculated packing energy. As such, it can be considered a reasonable model for solid beta-amyloid in Alzheimer's disease plaques. Interestingly, with the turn located at this position, the 1-43 structure is stabilized by a number of complementary intermolecular interactions between the beta-sheets. These well-defined interactions exist for the side-chain residues of 41, 42, and 43 with adjacent ABeta molecules. These interactions would not be conserved in the 1-40 peptide, and indeed, this enhanced interaction is proposed to give rise to the increased fibrillogenic nature of the ABeta 1-43 species over the 1-40 form. The models are used to explain the increased fibrillogenic nature of the Dutch family mutation of ABeta. These models are also employed to examine possible docking interactions of previously reported antiaggregation inhibitors, such as 4'-deoxy-4'-iododoxorubicin (IDOX) onto the theoretical growing surface. A docked structure of IDOX with the model of the solid fibril is described and a proposal for the mechanism of its antiaggregation properties is presented.

Alzheimer Disease↗

PubMed2004

Methods for generating high-resolution structural models from electron microscope tomography data.

Reconstructed volumes generated by tilt-image electron-microscope tomography offer the best spatial resolution currently available for studying cell structures in situ. Analysis is often accomplished by creating surface models that delineate grayscale contrast boundaries. Here, we introduce a specialized and convenient sequence of segmentation operations for making such models that greatly improves their reliability and spatial resolution as compared to current approaches, providing a basis for making accurate measurements. To assess the reliability of the surface models, we introduce a spatial uncertainty measurement based on grayscale gradient scale length. The model generation and measurement methods are validated by applying them to synthetic data, and their utility is demonstrated by using them to characterize macromolecular architecture of active zone material at the frog's neuromuscular junction.

Computer Simulation↗

PubMed2000

Development of a tertiary-structure model of the C-terminal domain of DPP IV.

Based on the recently published structure of prolyl oligopeptidase (POP) a model of the C-terminal part of dipeptidyl peptidase IV (DPP IV) which contains the active site has been developed. The structure of the model of DPP IV shows considerable similarity to the structure of POP particularly in the active site. A hydrophobic pocket (Tyr666, Tyr670, Tyr 631, Val556) forms the S1-binding site for recognition of proline. Tyr547 may stabilise the oxyanion formed in the tetrahedral intermediates by a strong hydrogen bond. The positively charged N-terminus of ligands of DPP IV is recognised by forming a salt bridge with the acidic side chain Glu668. A second hydrophobic pocket (S2' to S5') may represent an important binding site for HIV-1 Tat-protein derivatives, chemokines and others.

Amino Acid Sequence↗

PubMed2000

A structural model for predicting mathematics achievement: its relation with anxiety and self-concept in mathematics.

This study proposed and tested a model of mathematics achievement and its relations to antecedent and subsequent factors using structural equations modeling. A sample of elementary school students in Al-Ain school district (n = 394) completed an Arabic version of the Self-description Questionnaire as well as a questionnaire measuring their perception of the importance of mathematics, anxiety about it, and the amount of effort they exerted in studying. Mathematics grades were obtained from the official school records. Importance and effort were positively related to achievement which in turn had a positive path coefficient to self-concept and a negative path to anxiety. The hypothesized model explained 40%, 64%, and 73% of the variance in achievement, self-concept, and anxiety, respectively. The results can be interpreted as indicating that achievement is an important outcome and antecedent construct within the proposed model.

Achievement↗

PubMed2000

The active site of drosomycin, a small insect antifungal protein, delineated by comparison with the modeled structure of Rs-AFP2, a plant antifungal protein.

Drosomycin is the first strictly antifungal protein isolated from an insect (Drosophila melanogaster). The solution structure of this 44-residue protein has been reported previously. It involves a three-stranded beta-sheet and an alpha-helix, the protein global fold being maintained by four disulfide bridges. Rs-AFP2 is a plant antifungal protein exhibiting 41% sequence similarity with drosomycin. Mutational analysis of Rs-AFP2 showed the importance of some residues in the antifungal activity of the protein against the fungus target. In order to determine the structural features responsible for antifungal activity in both drosomycin and Rs-AFP2, we modeled the three-dimensional structure of Rs-AFP2, and of other antifungal proteins, using the solution structure of drosomycin as a template. Structure analysis of drosomycin and Rs-AFP2, and comparisons with the other modeled antifungal structures, revealed that the two proteins shared a hydrophobic cluster located at the protein surface in which a lysine residue is embedded. Based on these close structural similarities and the experimental data available for Rs-AFP2 mutants, an antifungal active site of the insect protein is proposed.

Amino Acid Sequence↗

PubMed2002

Human betacellulin structure modeled from other members of EGF family.

We have modeled betacellulin (BTC) to gain insight into the structural elements that can explain its properties. The epidermal growth factor (EGF) signal transduction pathway, a significant mediator of several cell functions, is based on four closely related tyrosine kinase receptors. The ErbB receptors are transmembrane glycoproteins and signal transduction is initiated by ligand binding that induces receptor homo- or heterodimerization to form a complex containing two molecules of ligand and two molecules of receptor. The EGF family of ligands can be divided into three groups based on their ability to bind and activate distinct ErbB receptor homo- and heterodimers. Each member of the group formed by BTC, heparin binding EGF (HB-EGF) and epiregulin (EP) can interact with both the EGF receptor (EGFR) and heregulin receptors (ErbB-3 and ErbB-4), and are hence called "bispecific" ligands. BTC and EP also present the distinctive feature that they activate all possible heterodimeric ErbB receptors. BTC has been modeled with the program MODELLER, using human EGF, human transforming growth factor alpha (hTGFalpha), human HB-EGF and human heregulin one alpha (hHRG-1alpha) as templates. The structure of the model as well as that of the templates were optimized and a simulation of 100 ps was run for all. The main structural properties of the model and the templates were compared and in conclusion the hBTC conformation was closely similar to that of hTGFalpha.

Amino Acid Sequence↗

PubMed2003

Primary and 3-D modelled structures of two cyclotides from Viola odorata.

Two polypeptides named vodo M and vodo N, both of 29 amino acids, have been isolated from Viola odorata L. (Violaceae) using ion exchange chromatography and reversed phase HPLC. The sequences were determined by automated Edman degradation, quantitative amino acid analysis, and mass spectrometry (MS). Using MS, it was established that vodo M (cyclo-SWPVCTRNGAPICGESCFTGKCYTVQCSC) and vodo N (cyclo-SWPVCYRNGLPVCGETCTLGKCYTAGCSC) form a head-to-tail cyclic backbone and that six cysteine residues are involved in three disulphide bonds. Their origin, sequences, and cyclic nature suggest that these peptides belong to the family of cyclic plant peptides, called cyclotides. The three-dimensional structures of vodo M and vodo N were modelled by homology, using the experimentally determined structure of the cyclotide kalata B1 as the template. The images of vodo M and vodo N show amphipathic structures with considerable surface hydrophobicity for a protein modelled in a polar environment.

Amino Acid Sequence↗

PubMedDate not supplied

A structural model of the substance use pathways among minority youth.

OBJECTIVE: To evaluate the substance use pathways of minority adolescents with a structural equation modeling (SEM) based on the social ecological model. METHOD: Seven hundred ninety adolescents completed the baseline survey questionnaire for the Center for Substance Abuse Prevention's Mentoring and Family Strengthening Initiative. The exogenous variables were family supervision, family involvement, and social support, whereas self-control, school connectedness, and substance use served as the endogenous variables. RESULTS: The following significant direct effects were found: family involvement to self-control; self-control and social support to school connectedness; school connectedness to substance use. CONCLUSIONS: These findings provide empirical evidence that family protective factors can significantly influence adolescents' substance use and should be adopted into substance use prevention interventions.

Adolescent↗